Is CRYBA4 p.Arg103Cys (c.307C>T) pathogenic?

CRYBA4 p.Arg103Cys (c.307C>T) is classified Benign/Likely benign in CRYBA4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-13). AlphaMissense: likely benign (0.1468); Rare (popmax 0.924%, afr); Associated with cataract 23.

What condition is associated with CRYBA4 p.Arg103Cys (c.307C>T)?

CRYBA4 p.Arg103Cys (c.307C>T) is associated with cataract 23 (ClinVar).

How common is CRYBA4 p.Arg103Cys (c.307C>T) in the general population?

CRYBA4 p.Arg103Cys (c.307C>T) is rare (popmax 0.924%, afr) (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.Arg103Cys (c.307C>T)?

AlphaMissense predicts likely benign (score 0.1468) — an in-silico prediction, not a clinical call.

CRYBA4 p.Arg103Cys

c.307C>T · rs149353652 · VCV474085

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1468 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.924%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cataract 23

Computational evidence

Protein change
AlphaMissense	0.1468	likely benign
REVEL	0.483	indeterminate
SaProt	LLR -7.09	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 2.9	GERP -2.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,887 bp · p 0.027 · regional, not allelic
Overall
CADD	26.7	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 0.924% African / African-American · 693/74,968 alleles

Filtering AF 0.867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.845%

Overall 0.0503% 812/1,613,908 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.924%	108
Remaining individualsnot grpmax-eligible	0.0752%	1,330
Admixed American	0.0267%	3,750
European (non-Finnish)	0.00458%	21,851
East Asian	0.00223%	44,864
South Asian	0.0011%	91,052

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.Arg103Cys
Coding: c.307C>T
MANE Select: NM_001886
dbSNP: rs149353652
Type: single nucleotide variant
Location: chr22:26628294 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 103: an α-helix; the 'connecting peptide' region

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

CRYBB1 p.Ala103Pro Uncertain significance ★ ⚠ same residue
CRYBB1 p.Ala103Thr Uncertain significance ★ same residue
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

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-arg103cys (accessed [today's date]).

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