Is CRYBB3 p.Ala2= (c.6G>A) pathogenic?

CRYBB3 p.Ala2= (c.6G>A) is classified Benign/Likely benign in CRYBB3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-04). Rare (popmax 0.437%, afr); Associated with cataract 22 multiple types.

What condition is associated with CRYBB3 p.Ala2= (c.6G>A)?

CRYBB3 p.Ala2= (c.6G>A) is associated with cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Ala2= (c.6G>A) in the general population?

CRYBB3 p.Ala2= (c.6G>A) is rare (popmax 0.437%, 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.

CRYBB3 p.Ala2=

c.6G>A · rs144393956 · VCV703368

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.437%, afr)

Conditions

cataract 22 multiple types

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 -11	GERP -2.7
Overall
CADD	0.251	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.437% African / African-American · 328/74,996 alleles

Filtering AF 0.398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.383%

Overall 0.0774% 1,249/1,613,314 alleles · rare exomes 989/1,461,074 · genomes 260/152,240 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.71%	59
African / African-Americangrpmax	0.437%	229
Remaining individualsnot grpmax-eligible	0.16%	625
Middle Eastern	0.0828%	1,208
Admixed American	0.0817%	1,224
European (non-Finnish)	0.0221%	4,519
South Asian	0.0011%	91,062

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CRYBB3
Protein: p.Ala2=
Coding: c.6G>A
MANE Select: NM_004076
dbSNP: rs144393956
Type: single nucleotide variant
Location: chr22:25201402 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 2: a modified residue (n-acetylalanine; in beta-crystallin b3, n-terminally processed); the 'n-terminal arm' region

Full CRYBB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 22 multiple types — 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

CRYBB3 p.Ala2Val Uncertain significance ★ ⚠ same residue
CRYBB3 p.Arg127Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg127His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg152Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg169Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg179His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg207His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg75Cys Uncertain significance ★★ ⚠ 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/crybb3-p-ala2 (accessed [today's date]).

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