Is OCA2 p.Leu447Pro (c.1340T>C) pathogenic?

OCA2 p.Leu447Pro (c.1340T>C) is classified Conflicting classifications of pathogenicity in OCA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.9849); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with OCA2 p.Leu447Pro (c.1340T>C)?

OCA2 p.Leu447Pro (c.1340T>C) is associated with Inborn genetic diseases (ClinVar).

How common is OCA2 p.Leu447Pro (c.1340T>C) in the general population?

OCA2 p.Leu447Pro (c.1340T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OCA2 p.Leu447Pro (c.1340T>C)?

AlphaMissense predicts likely pathogenic (score 0.9849) — an in-silico prediction, not a clinical call.

OCA2 p.Leu447Pro

c.1340T>C · rs2548345135 · VCV2394236

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9849 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9849	likely pathogenic · top 3% in OCA2
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -16.55	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 326 kb · p 0.41 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OCA2
Protein: p.Leu447Pro
Coding: c.1340T>C
MANE Select: NM_000275
dbSNP: rs2548345135
Type: single nucleotide variant
Location: chr15:27985088 (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.Leu447= Likely benign ★ same residue
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

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-leu447pro (accessed [today's date]).

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