Is OCA2 p.Arg595Ser (c.1785A>T) pathogenic?

OCA2 p.Arg595Ser (c.1785A>T) is classified Uncertain significance in OCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). AlphaMissense: likely benign (0.3306); Very rare (popmax 0.00534%, afr).

How common is OCA2 p.Arg595Ser (c.1785A>T) in the general population?

OCA2 p.Arg595Ser (c.1785A>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about OCA2 p.Arg595Ser (c.1785A>T)?

AlphaMissense predicts likely benign (score 0.3306) — an in-silico prediction, not a clinical call.

OCA2 p.Arg595Ser

c.1785A>T · VCV3716940

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3306 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3306	likely benign
REVEL	0.65	pathogenic-leaning
SaProt	LLR -6.90	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 0.64	GERP -0.35, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 326 kb · p 0.41 · regional, not allelic
Overall
CADD	22.4	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 0.00534% African / African-American · 4/74,900 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000311% 5/1,608,528 alleles · very rare exomes 2/1,456,234 · genomes 3/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,725
Remaining individualsnot grpmax-eligible	0.0016%	62,332

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.Arg595Ser
Coding: c.1785A>T
MANE Select: NM_000275
Type: single nucleotide variant
Location: chr15:27955215 (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.Arg595= Uncertain significance ★ 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
OCA2 c.1239+2T>A Likely pathogenic ★★ same type
OCA2 c.1365-1G>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-arg595ser (accessed [today's date]).

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