Is CRYBA4 p.Ala9= (c.27G>A) pathogenic?

CRYBA4 p.Ala9= (c.27G>A) is classified Likely benign in CRYBA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-15). Very rare (popmax 0.00833%, amr); Associated with cataract 23.

What condition is associated with CRYBA4 p.Ala9= (c.27G>A)?

CRYBA4 p.Ala9= (c.27G>A) is associated with cataract 23 (ClinVar).

How common is CRYBA4 p.Ala9= (c.27G>A) in the general population?

CRYBA4 p.Ala9= (c.27G>A) is very rare (popmax 0.00833%, 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.

CRYBA4 p.Ala9=

c.27G>A · rs773497792 · VCV2697293

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Conditions

cataract 23

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.6	GERP -2.5
Overall
CADD	1.574	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/59,996 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00298% 48/1,613,248 alleles · very rare exomes 45/1,461,314 · genomes 3/151,934 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	11,999
European (non-Finnish)	0.00322%	31,039
Remaining individualsnot grpmax-eligible	0.0032%	31,232
African / African-American	0.00267%	37,404
South Asian	0.0011%	91,064

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.Ala9=
Coding: c.27G>A
MANE Select: NM_001886
dbSNP: rs773497792
Type: single nucleotide variant
Location: chr22:26622623 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 9: the 'n-terminal arm' 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

CRYBA4 p.Ala9Val 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
CRYBA4 p.Arg103Cys 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-ala9 (accessed [today's date]).

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