Is CRYBB3 p.Arg88His (c.263G>A) pathogenic?

CRYBB3 p.Arg88His (c.263G>A) is classified Uncertain significance in CRYBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-31). AlphaMissense: likely benign (0.2197); Rare (popmax 0.188%, afr); Associated with cataract 22 multiple types.

What condition is associated with CRYBB3 p.Arg88His (c.263G>A)?

CRYBB3 p.Arg88His (c.263G>A) is associated with cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Arg88His (c.263G>A) in the general population?

CRYBB3 p.Arg88His (c.263G>A) is rare (popmax 0.188%, 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.Arg88His (c.263G>A)?

AlphaMissense predicts likely benign (score 0.2197) — an in-silico prediction, not a clinical call.

CRYBB3 p.Arg88His

c.263G>A · rs138167578 · VCV1003766

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2197 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.188%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cataract 22 multiple types

Computational evidence

Protein change
AlphaMissense	0.2197	likely benign
REVEL	0.589	indeterminate
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.65, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	26.0	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 0.188% African / African-American · 141/75,040 alleles

Filtering AF 0.163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.153%

Overall 0.0103% 167/1,614,182 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.188%	532
Admixed American	0.0117%	8,574
Remaining individualsnot grpmax-eligible	0.0096%	10,418
South Asian	0.00439%	22,770
European (non-Finnish)	0.000763%	131,115

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.Arg88His
Coding: c.263G>A
MANE Select: NM_004076
dbSNP: rs138167578
Type: single nucleotide variant
Location: chr22:25203831 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 88: 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.Arg88Cys 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-arg88his (accessed [today's date]).

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