Is OCA2 p.Leu417Pro (c.1250T>C) pathogenic?

OCA2 p.Leu417Pro (c.1250T>C) is classified Likely pathogenic in OCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: likely pathogenic (0.7995); Very rare (popmax 0.00223%, eas); Associated with SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES.

What condition is associated with OCA2 p.Leu417Pro (c.1250T>C)?

OCA2 p.Leu417Pro (c.1250T>C) is associated with SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES, oculocutaneous albinism type 2 (ClinVar).

How common is OCA2 p.Leu417Pro (c.1250T>C) in the general population?

OCA2 p.Leu417Pro (c.1250T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about OCA2 p.Leu417Pro (c.1250T>C)?

AlphaMissense predicts likely pathogenic (score 0.7995) — an in-silico prediction, not a clinical call.

OCA2 p.Leu417Pro

c.1250T>C · VCV4077119

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES

Computational evidence

Protein change
AlphaMissense	0.7995	likely pathogenic ✓ concordant with ClinVar
REVEL	0.723	pathogenic-leaning
SaProt	LLR -14.40	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 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 326 kb · p 0.41 · regional, not allelic
Overall
CADD	27.9	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 0.00223% East Asian · 1/44,874 alleles

Overall 0.000124% 2/1,613,764 alleles · very rare exomes 2/1,461,452 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,874
African / African-American	0.00133%	75,056

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.Leu417Pro
Coding: c.1250T>C
MANE Select: NM_000275
Type: single nucleotide variant
Location: chr15:27985178 (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

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: oculocutaneous albinism type 2

Similar variants

OCA2 p.Leu417fs Pathogenic/Likely pathogenic ★★ same residue
OCA2 c.1044+1G>T Pathogenic ★★ same condition
OCA2 c.1045-15T>G Pathogenic/Likely pathogenic ★★ same condition
OCA2 c.1116+2T>C Likely pathogenic ★★ same condition
OCA2 c.1182+1G>A Pathogenic ★★ same condition
OCA2 c.1365-1G>A Pathogenic ★★ same condition
OCA2 c.1503+5G>A Pathogenic/Likely pathogenic ★★ same condition
OCA2 c.1504-2A>G Pathogenic/Likely pathogenic ★★ 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-leu417pro (accessed [today's date]).

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