Is CRYBA4 p.Ala53Val (c.158C>T) pathogenic?

CRYBA4 p.Ala53Val (c.158C>T) is classified Uncertain significance in CRYBA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-16). AlphaMissense: likely benign (0.1653); Very rare (popmax 0.005%, amr); Associated with cataract 23.

What condition is associated with CRYBA4 p.Ala53Val (c.158C>T)?

CRYBA4 p.Ala53Val (c.158C>T) is associated with cataract 23 (ClinVar).

How common is CRYBA4 p.Ala53Val (c.158C>T) in the general population?

CRYBA4 p.Ala53Val (c.158C>T) is very rare (popmax 0.005%, amr) (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.Ala53Val (c.158C>T)?

AlphaMissense predicts likely benign (score 0.1653) — an in-silico prediction, not a clinical call.

CRYBA4 p.Ala53Val

c.158C>T · VCV3704651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cataract 23

Computational evidence

Protein change
AlphaMissense	0.1653	likely benign
REVEL	0.552	indeterminate
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,887 bp · p 0.027 · regional, not allelic
Overall
CADD	27.7	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 0.005% Admixed American · 3/59,984 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000745% 12/1,610,982 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,995
African / African-American	0.00134%	74,852
South Asian	0.0011%	91,030
European (non-Finnish)	0.000595%	168,196

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.Ala53Val
Coding: c.158C>T
MANE Select: NM_001886
Type: single nucleotide variant
Location: chr22:26623352 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 53: 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-ala53val (accessed [today's date]).

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