Is MTHFS p.Ser12Arg (c.36C>A) pathogenic?

MTHFS p.Ser12Arg (c.36C>A) is classified Likely benign in MTHFS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely benign (0.3147); Rare (popmax 0.288%, afr).

How common is MTHFS p.Ser12Arg (c.36C>A) in the general population?

MTHFS p.Ser12Arg (c.36C>A) is rare (popmax 0.288%, afr) (gnomAD).

What do computational predictors say about MTHFS p.Ser12Arg (c.36C>A)?

AlphaMissense predicts likely benign (score 0.3147) — an in-silico prediction, not a clinical call.

MTHFS p.Ser12Arg

c.36C>A · rs200983403 · VCV2067208

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3147 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.288%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3147	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -5.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	phastCons 0.92
Regional constraint	o/e 0.98	unconstrained · MANE · 52 kb · p 0.7 · regional, not allelic
Overall
CADD	16.67	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.288% African / African-American · 209/72,446 alleles

Filtering AF 0.256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.244%

Overall 0.0141% 216/1,536,522 alleles · rare exomes 80/1,384,220 · genomes 136/152,302 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.288%	347
Remaining individualsnot grpmax-eligible	0.00669%	14,944
Admixed American	0.00589%	16,969

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MTHFS
Protein: p.Ser12Arg
Coding: c.36C>A
MANE Select: NM_006441
dbSNP: rs200983403
Type: single nucleotide variant
Location: chr15:79896953 (GRCh38)
Gene constraint: LOEUF 0.992 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 95.35 · 4 PDB
Residue 12: a binding site; an α-helix

Full MTHFS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTHFS p.Ser12Ile Uncertain significance ★★ ⚠ same residue
MTHFS p.Ser12Asn Uncertain significance ★ ⚠ same residue
MTHFS c.117+7G>C Benign/Likely benign ★★ same type
MTHFS p.Asp140= Benign ★★ same type
MTHFS p.Lys18= Benign/Likely benign ★★ same type
MTHFS p.Arg74Ter Pathogenic ★ same type
MTHFS p.Gln162Ter Likely pathogenic ★ same type
MTHFS p.Lys106Ter Pathogenic ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mthfs-p-ser12arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown