Is CRYBB3 p.Arg96His (c.287G>A) pathogenic?

CRYBB3 p.Arg96His (c.287G>A) is classified Conflicting classifications of pathogenicity in CRYBB3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-12-13). AlphaMissense: likely benign (0.0695); Ultra-rare (popmax 0.0242%, sas); Associated with cataract 22 multiple types.

What condition is associated with CRYBB3 p.Arg96His (c.287G>A)?

CRYBB3 p.Arg96His (c.287G>A) is associated with cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Arg96His (c.287G>A) in the general population?

CRYBB3 p.Arg96His (c.287G>A) is ultra-rare (popmax 0.0242%, sas) (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.Arg96His (c.287G>A)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

CRYBB3 p.Arg96His

c.287G>A · rs113872601 · VCV2819792

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 22 multiple types

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -2.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	GERP -3.4, phastCons 0.001
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	6.084	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 0.0242% South Asian · 22/91,090 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.0044% 71/1,614,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,140
African / African-American	0.0227%	4,414
Remaining individualsnot grpmax-eligible	0.0144%	6,946
Admixed American	0.00666%	15,006
European (non-Finnish)	0.00161%	62,106

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.Arg96His
Coding: c.287G>A
MANE Select: NM_004076
dbSNP: rs113872601
Type: single nucleotide variant
Location: chr22:25203855 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 96: a β-strand; the beta/gamma crystallin 'greek key' 2 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-arg96his (accessed [today's date]).

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