Is MTHFD2 p.Val205Ile (c.613G>A) pathogenic?

MTHFD2 p.Val205Ile (c.613G>A) is classified Uncertain significance in MTHFD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: ambiguous (0.4292); Very rare (popmax 0.0033%, sas).

How common is MTHFD2 p.Val205Ile (c.613G>A) in the general population?

MTHFD2 p.Val205Ile (c.613G>A) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about MTHFD2 p.Val205Ile (c.613G>A)?

AlphaMissense predicts ambiguous (score 0.4292) — an in-silico prediction, not a clinical call.

MTHFD2 p.Val205Ile

c.613G>A · VCV4111797

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4292 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Computational evidence

Protein change
AlphaMissense	0.4292	ambiguous
REVEL	0.451	indeterminate
SaProt	LLR -11.33	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 16 kb · p 6.7e-06 · regional, not allelic
Overall
CADD	30.0	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 0.0033% South Asian · 3/91,044 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00118% 19/1,613,672 alleles · very rare exomes 19/1,461,398 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,348
European (non-Finnish)	0.00136%	73,735

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: MTHFD2
Protein: p.Val205Ile
Coding: c.613G>A
MANE Select: NM_006636
Type: single nucleotide variant
Location: chr2:74209992 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.66 · 16 PDB
Residue 205: a turn

Full MTHFD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTHFD2 p.Ala12Ser Uncertain significance ★ ⚠ same type
MTHFD2 p.Ala12Val Uncertain significance ★ ⚠ same type
MTHFD2 p.Ala218Thr Uncertain significance ★ ⚠ same type
MTHFD2 p.Ala254Ser Uncertain significance ★ ⚠ same type
MTHFD2 p.Ala327Gly Uncertain significance ★ ⚠ same type
MTHFD2 p.Ala91Val Uncertain significance ★ ⚠ same type
MTHFD2 p.Arg13Leu Uncertain significance ★ ⚠ same type
MTHFD2 p.Arg26Cys Uncertain significance ★ ⚠ 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/mthfd2-p-val205ile (accessed [today's date]).

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