Is OCA2 p.Asp486His (c.1456G>C) pathogenic?

OCA2 p.Asp486His (c.1456G>C) is classified Uncertain significance in OCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely pathogenic (0.986); Very rare (popmax 8.47e-05%, nfe).

How common is OCA2 p.Asp486His (c.1456G>C) in the general population?

OCA2 p.Asp486His (c.1456G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about OCA2 p.Asp486His (c.1456G>C)?

AlphaMissense predicts likely pathogenic (score 0.986) — an in-silico prediction, not a clinical call.

OCA2 p.Asp486His

c.1456G>C · VCV3895926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.986	likely pathogenic · top 3% in OCA2
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 326 kb · p 0.41 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,170 alleles · very rare exomes 0/1,461,886 · genomes 1/152,284 · 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.Asp486His
Coding: c.1456G>C
MANE Select: NM_000275
Type: single nucleotide variant
Location: chr15:27983392 (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

Similar variants

OCA2 p.Asp486Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
OCA2 p.Asp486= Likely benign ★ same residue
OCA2 p.Asp486fs Pathogenic/Likely pathogenic ★★ 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
OCA2 c.1182+1G>A 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-asp486his (accessed [today's date]).

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