Is OCA2 p.Phe684Cys (c.2051T>G) pathogenic?

OCA2 p.Phe684Cys (c.2051T>G) is classified Uncertain significance in OCA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.9804); Very rare (popmax 0.00661%, nfe); Associated with OCA2-related disorder.

What condition is associated with OCA2 p.Phe684Cys (c.2051T>G)?

OCA2 p.Phe684Cys (c.2051T>G) is associated with OCA2-related disorder (ClinVar).

How common is OCA2 p.Phe684Cys (c.2051T>G) in the general population?

OCA2 p.Phe684Cys (c.2051T>G) is very rare (popmax 0.00661%, nfe) (gnomAD).

What do computational predictors say about OCA2 p.Phe684Cys (c.2051T>G)?

AlphaMissense predicts likely pathogenic (score 0.9804) — an in-silico prediction, not a clinical call.

OCA2 p.Phe684Cys

c.2051T>G · rs772754008 · VCV2137630

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9804 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00661%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

OCA2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9804	likely pathogenic · top 4% in OCA2
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -16.89	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	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 326 kb · p 0.41 · regional, not allelic
Overall
CADD	27.8	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 0.00661% European (non-Finnish) · 78/1,180,002 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00489% 79/1,614,026 alleles · very rare exomes 76/1,461,810 · genomes 3/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00661%	15,128
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Phe684Cys
Coding: c.2051T>G
MANE Select: NM_000275
dbSNP: rs772754008
Type: single nucleotide variant
Location: chr15:27926155 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.79
Residue 684: 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.Phe684Val Likely pathogenic ★ 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
OCA2 c.1504-2A>G Pathogenic/Likely pathogenic ★★ same condition
OCA2 c.1784+1G>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-phe684cys (accessed [today's date]).

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