Is OCA2 p.Met425Val (c.1273A>G) pathogenic?

OCA2 p.Met425Val (c.1273A>G) is classified Uncertain significance in OCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-10). AlphaMissense: likely benign (0.3091); Ultra-rare (popmax 0.012%, afr).

How common is OCA2 p.Met425Val (c.1273A>G) in the general population?

OCA2 p.Met425Val (c.1273A>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about OCA2 p.Met425Val (c.1273A>G)?

AlphaMissense predicts likely benign (score 0.3091) — an in-silico prediction, not a clinical call.

OCA2 p.Met425Val

c.1273A>G · rs201484597 · VCV1497912

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3091 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3091	likely benign
REVEL	0.725	pathogenic-leaning
SaProt	LLR -8.90	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 326 kb · p 0.41 · regional, not allelic
Overall
CADD	25.1	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 0.012% African / African-American · 9/74,918 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000558% 9/1,613,758 alleles · ultra-rare exomes 3/1,461,578 · genomes 6/152,180 · joint denominator

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: OCA2
Protein: p.Met425Val
Coding: c.1273A>G
MANE Select: NM_000275
dbSNP: rs201484597
Type: single nucleotide variant
Location: chr15:27985155 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.79
Residue 425: a UniProt-annotated variant site (in oca2; mild)

Full OCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

OCA2 p.Met425Thr Uncertain significance ★★ ⚠ same residue
OCA2 p.Met425Ile Uncertain significance ★ ⚠ same residue
OCA2 p.Met425fs Likely pathogenic ★ same residue
OCA2 p.Met425del Conflicting classifications of pathogenicity ★ same residue
OCA2 c.1044+1G>T Pathogenic ★★ same type
OCA2 c.1044+2T>C Pathogenic/Likely pathogenic ★★ same type
OCA2 c.1045-15T>G Pathogenic/Likely pathogenic ★★ same type
OCA2 c.1116+2T>C Likely 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/oca2-p-met425val (accessed [today's date]).

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