Is OCA2 p.Ile400Met (c.1200A>G) pathogenic?

OCA2 p.Ile400Met (c.1200A>G) is classified Uncertain significance in OCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: likely benign (0.2408); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with OCA2 p.Ile400Met (c.1200A>G)?

OCA2 p.Ile400Met (c.1200A>G) is associated with Inborn genetic diseases (ClinVar).

How common is OCA2 p.Ile400Met (c.1200A>G) in the general population?

OCA2 p.Ile400Met (c.1200A>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about OCA2 p.Ile400Met (c.1200A>G)?

AlphaMissense predicts likely benign (score 0.2408) — an in-silico prediction, not a clinical call.

OCA2 p.Ile400Met

c.1200A>G · VCV3923790

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2408	likely benign
REVEL	0.628	indeterminate
SaProt	LLR -12.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.43	GERP 0.71, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 326 kb · p 0.41 · regional, not allelic
Overall
CADD	22.8	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 0.005% Admixed American · 3/59,996 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000188% 3/1,593,798 alleles · very rare exomes 3/1,441,514 · genomes 0/152,284 · 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.Ile400Met
Coding: c.1200A>G
MANE Select: NM_000275
Type: single nucleotide variant
Location: chr15:27986626 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.79

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OCA2 p.Ala334Thr Pathogenic/Likely pathogenic ★★ same condition
OCA2 p.Gly775Arg Pathogenic ★★ same condition
OCA2 p.Ala185Ser Uncertain significance ★★ ⚠ same condition
OCA2 p.Ala339Val Uncertain significance ★★ ⚠ same condition
OCA2 p.Ala343Thr Uncertain significance ★★ ⚠ same condition
OCA2 p.Ala433Thr Uncertain significance ★★ ⚠ same condition
OCA2 p.Ala433Val Uncertain significance ★★ ⚠ same condition
OCA2 p.Ala587Thr Uncertain significance ★★ ⚠ same condition

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-ile400met (accessed [today's date]).

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