Is CRYBA4 p.Ser76Thr (c.227G>C) pathogenic?

CRYBA4 p.Ser76Thr (c.227G>C) is classified Uncertain significance in CRYBA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-23). AlphaMissense: likely benign (0.0942); Ultra-rare (popmax 0.029%, eas); Associated with cataract 23.

What condition is associated with CRYBA4 p.Ser76Thr (c.227G>C)?

CRYBA4 p.Ser76Thr (c.227G>C) is associated with cataract 23 (ClinVar).

How common is CRYBA4 p.Ser76Thr (c.227G>C) in the general population?

CRYBA4 p.Ser76Thr (c.227G>C) is ultra-rare (popmax 0.029%, eas) (gnomAD).

How is Early onset non-syndromic cataract inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CRYBA4 p.Ser76Thr (c.227G>C)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

CRYBA4 p.Ser76Thr

c.227G>C · rs776573050 · VCV661895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 23

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -7.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.3, phastCons 0.077
Regional constraint	o/e 0.86	unconstrained · MANE · 7,887 bp · p 0.027 · regional, not allelic
Overall
CADD	8.495	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.029% East Asian · 13/44,894 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.000929% 15/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,453
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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: CRYBA4
Protein: p.Ser76Thr
Coding: c.227G>C
MANE Select: NM_001886
dbSNP: rs776573050
Type: single nucleotide variant
Location: chr22:26625549 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 76: the beta/gamma crystallin 'greek key' 2 domain

Full CRYBA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 23 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

CRYBA4 p.Phe22Ser Uncertain significance ★★ ⚠ same condition
CRYBA4 p.Phe57Val Uncertain significance ★★ ⚠ same condition
CRYBA4 c.159-20A>G Benign ★★ same condition
CRYBA4 c.300+3A>G Benign ★★ same condition
CRYBA4 c.40-1G>C Benign/Likely benign ★★ same condition
CRYBA4 c.444-18G>A Benign ★★ same condition
CRYBA4 p.Arg103Cys Benign/Likely benign ★★ same condition
CRYBA4 p.Gly72= Benign/Likely benign ★★ 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/cryba4-p-ser76thr (accessed [today's date]).

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