Is OCA2 p.Pro211Ala (c.631C>G) pathogenic?

OCA2 p.Pro211Ala (c.631C>G) is classified Pathogenic/Likely pathogenic in OCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.1017); Very rare (popmax 0.000763%, nfe); Associated with OCA2-related disorder.

What condition is associated with OCA2 p.Pro211Ala (c.631C>G)?

OCA2 p.Pro211Ala (c.631C>G) is associated with OCA2-related disorder (ClinVar).

How common is OCA2 p.Pro211Ala (c.631C>G) in the general population?

OCA2 p.Pro211Ala (c.631C>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about OCA2 p.Pro211Ala (c.631C>G)?

AlphaMissense predicts likely benign (score 0.1017) — an in-silico prediction, not a clinical call.

OCA2 p.Pro211Ala

c.631C>G · rs777893926 · VCV1388959

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

OCA2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1017	likely benign ⚠ discordant with ClinVar
REVEL	0.465	indeterminate
SaProt	LLR -10.44	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 8.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 326 kb · p 0.41 · regional, not allelic
Overall
CADD	22.5	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 0.000763% European (non-Finnish) · 9/1,179,434 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000806% 13/1,613,238 alleles · very rare exomes 11/1,461,072 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,614
European (non-Finnish)grpmax	0.000763%	131,048

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro211Ala
Coding: c.631C>G
MANE Select: NM_000275
dbSNP: rs777893926
Type: single nucleotide variant
Location: chr15:28022516 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.79
Residue 211: a UniProt-annotated variant site (in oca2; severe); a UniProt-annotated variant site (in oca2)

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

Disease context

OCA2-related disorder

Similar variants

OCA2 p.Pro211Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
OCA2 p.Pro211= Likely benign ★★ same residue
OCA2 p.Pro211Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
OCA2 c.1044+1G>T Pathogenic ★★ same condition
OCA2 c.1044+2T>C Pathogenic/Likely pathogenic ★★ same condition
OCA2 c.1045-15T>G Pathogenic/Likely pathogenic ★★ same condition
OCA2 c.1239+2T>A Likely pathogenic ★★ same condition
OCA2 c.1503+5G>A 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-pro211ala (accessed [today's date]).

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