Is CRYBA2 p.Ser191Pro (c.571T>C) pathogenic?

CRYBA2 p.Ser191Pro (c.571T>C) is classified Conflicting classifications of pathogenicity in CRYBA2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.9764); Ultra-rare (popmax 0.077%, nfe); Associated with early-onset anterior polar cataract.

What condition is associated with CRYBA2 p.Ser191Pro (c.571T>C)?

CRYBA2 p.Ser191Pro (c.571T>C) is associated with early-onset anterior polar cataract (ClinVar).

How common is CRYBA2 p.Ser191Pro (c.571T>C) in the general population?

CRYBA2 p.Ser191Pro (c.571T>C) is ultra-rare (popmax 0.077%, nfe) (gnomAD).

What do computational predictors say about CRYBA2 p.Ser191Pro (c.571T>C)?

AlphaMissense predicts likely pathogenic (score 0.9764) — an in-silico prediction, not a clinical call.

CRYBA2 p.Ser191Pro

c.571T>C · rs144661907 · VCV2515408

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9764 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.077%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-onset anterior polar cataract

Computational evidence

Protein change
AlphaMissense	0.9764	likely pathogenic · top 2% in CRYBA2
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -14.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,921 bp · p 0.71 · regional, not allelic
Overall
CADD	27.2	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 0.077% European (non-Finnish) · 909/1,179,986 alleles

Filtering AF 0.0728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0712%

Overall 0.0579% 934/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.077%	1,298
Remaining individualsnot grpmax-eligible	0.016%	6,248
African / African-American	0.012%	8,319
Finnishnot grpmax-eligible	0.00469%	21,344
Admixed American	0.00333%	30,004
South Asian	0.0011%	91,086

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: CRYBA2
Protein: p.Ser191Pro
Coding: c.571T>C
MANE Select: NM_057093
dbSNP: rs144661907
Type: single nucleotide variant
Location: chr2:218990275 (GRCh38)
Gene constraint: LOEUF 1.372 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12
Residue 191: the beta/gamma crystallin 'greek key' 4 domain

Full CRYBA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

early-onset anterior polar cataract — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYBA2 p.Ala34Glu Uncertain significance ★ ⚠ same condition
CRYBA2 p.Ala80Thr Uncertain significance ★★ ⚠ same type
CRYBA2 c.303+127A>G Benign ★★ same type
CRYBA2 c.304-16T>C Benign ★★ same type
CRYBA2 c.303+5G>A Uncertain significance ★ same type
CRYBA2 c.446+1G>A Uncertain significance ★ same type
CRYBA2 p.Ala10Pro Uncertain significance ★ ⚠ same type
CRYBA2 p.Ala6Ser Uncertain significance ★ ⚠ 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/cryba2-p-ser191pro (accessed [today's date]).

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