Is CRYBA4 p.Ala97Val (c.290C>T) pathogenic?

CRYBA4 p.Ala97Val (c.290C>T) is classified Likely benign in CRYBA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-28). AlphaMissense: likely benign (0.0338); Rare (popmax 0.163%, sas); Associated with cataract 23.

What condition is associated with CRYBA4 p.Ala97Val (c.290C>T)?

CRYBA4 p.Ala97Val (c.290C>T) is associated with cataract 23 (ClinVar).

How common is CRYBA4 p.Ala97Val (c.290C>T) in the general population?

CRYBA4 p.Ala97Val (c.290C>T) is rare (popmax 0.163%, sas) (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.Ala97Val (c.290C>T)?

AlphaMissense predicts likely benign (score 0.0338) — an in-silico prediction, not a clinical call.

CRYBA4 p.Ala97Val

c.290C>T · rs150525825 · VCV766809

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0338 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.163%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 23

Computational evidence

Protein change
AlphaMissense	0.0338	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -0.73	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 2.9	GERP 0.81, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,887 bp · p 0.027 · regional, not allelic
Overall
CADD	20.1	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 0.163% South Asian · 148/91,042 alleles

Filtering AF 0.141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.133%

Overall 0.0157% 254/1,613,704 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.163%	615
Middle Eastern	0.116%	865
Remaining individualsnot grpmax-eligible	0.0144%	6,944
European (non-Finnish)	0.00695%	14,389
Admixed American	0.00667%	15,001
Finnishnot grpmax-eligible	0.00471%	21,253
East Asian	0.00223%	44,874

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.Ala97Val
Coding: c.290C>T
MANE Select: NM_001886
dbSNP: rs150525825
Type: single nucleotide variant
Location: chr22:26625612 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 97: 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-ala97val (accessed [today's date]).

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