Is CRYBB3 p.Glu32Asp (c.96G>T) pathogenic?

CRYBB3 p.Glu32Asp (c.96G>T) is classified Conflicting classifications of pathogenicity in CRYBB3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely pathogenic (0.7109); Rare (popmax 0.35%, afr); Associated with cataract 22 multiple types.

What condition is associated with CRYBB3 p.Glu32Asp (c.96G>T)?

CRYBB3 p.Glu32Asp (c.96G>T) is associated with cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Glu32Asp (c.96G>T) in the general population?

CRYBB3 p.Glu32Asp (c.96G>T) is rare (popmax 0.35%, 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 CRYBB3 p.Glu32Asp (c.96G>T)?

AlphaMissense predicts likely pathogenic (score 0.7109) — an in-silico prediction, not a clinical call.

CRYBB3 p.Glu32Asp

c.96G>T · rs142996620 · VCV1955730

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7109 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.35%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 22 multiple types

Computational evidence

Protein change
AlphaMissense	0.7109	likely pathogenic
REVEL	0.698	pathogenic-leaning
SaProt	LLR -8.89	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -0.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	25.0	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 0.35% African / African-American · 263/75,060 alleles

Filtering AF 0.316% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.302%

Overall 0.0183% 295/1,614,052 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.35%	285
Middle Eastern	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0192%	5,208
Admixed American	0.0183%	5,457
South Asian	0.0022%	45,532
European (non-Finnish)	0.000424%	235,997

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.Glu32Asp
Coding: c.96G>T
MANE Select: NM_004076
dbSNP: rs142996620
Type: single nucleotide variant
Location: chr22:25202694 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 32: an α-helix; the beta/gamma crystallin 'greek key' 1 domain

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.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
CRYBB3 p.Arg75His 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-glu32asp (accessed [today's date]).

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