In the case of MTHFR there's a lot of solid research into the missense mutations which cause reduced enzyme activity. While many SNPs (especially non-coding ones) on many genes are prone to having vague, contradictory, and low-quality support for their impact, that is not always the case.
It's been found pretty consistently that MTHFR C677T (rs1801133), for example, results in 70% reduction in enzyme activity when homozygous, and about 35% reduction in enzyme activity when heterozygous. Numerous studies consistently associate this with a modest elevation in various health risks: elevated homocysteine, and various folate-related birth defects when the mother has a mutation.
Things can and do get a bit crazy at that point, and some people then engage in various histrionics about their "broken" genes and the need to spend a lot of money on low-dose Yasko supplements which ironically don't even take into account the reduced ability to convert inactive (and cheap) folic acid into an active (and expensive) form. But again we can go back to the research, and find a couple of papers which show that people with these mutations completely remove the elevated risk factor if they supplement with an active folate or simply eat a respectable amount of vegetables as part of their regular diet.
The other common source of passionate misunderstandings is that people assume that having one of these mutations is exactly equivalent to having a disease, and that they are "diagnosed with having MTHFR" or similar. But if we look at prevalence rates of these mutations, it's obvious that they're far more common than any disease (or all diseases), and people usually live with them with little or no problem. On average, people have a 30-40% reduction in MTHFR gene function compared to optimal function. Hence it's nothing to get excited about when someone joins the 10% of the population with MTHFR C677T +/+. Just take a supplement or eat some damned vegetables, especially during pregnancy. Problem solved.
theres one thing you didn't mention that I believe is a big factor with mthfr (and probably others)- aging and its effect on whatever bad SNPs they may have.
both my sister and myself starting having really bad issues when she was in late 40s and I was in my early 50s.
but looking back I can see periods of my life that probably were complicated by mthfr.
hypergonadism, anemia, thyroid at bottom of normal for the past two decades and doctors unable to explain.
all progressively worse as I got older and increased by exercise and physical activity.
I must have spent a thousand or two on supplements without getting anywhere, not until I found out that supporting with mitochondrial and methylation factors made a big difference.
for what its worth, my sister takes Metanx once a day since she found out and does well on it.
also one other thing re mthfr.
high homocysteine levels are not always a reliable marker for mthfr issues.
I'm the exception that proves the rule, normal homocysteine when they checked a few years ago, which all the doctors have used to say mthfr is not an issue with me.