Is CRYBB1 p.Arg230Ser (c.688C>A) pathogenic?

CRYBB1 p.Arg230Ser (c.688C>A) is classified Uncertain significance in CRYBB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). AlphaMissense: likely pathogenic (0.9827); Ultra-rare (popmax 0.0312%, eas); Associated with cataract 17 multiple types.

What condition is associated with CRYBB1 p.Arg230Ser (c.688C>A)?

CRYBB1 p.Arg230Ser (c.688C>A) is associated with cataract 17 multiple types (ClinVar).

How common is CRYBB1 p.Arg230Ser (c.688C>A) in the general population?

CRYBB1 p.Arg230Ser (c.688C>A) is ultra-rare (popmax 0.0312%, eas) (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 CRYBB1 p.Arg230Ser (c.688C>A)?

AlphaMissense predicts likely pathogenic (score 0.9827) — an in-silico prediction, not a clinical call.

CRYBB1 p.Arg230Ser

c.688C>A · rs762942964 · VCV901235

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 17 multiple types

Computational evidence

Protein change
AlphaMissense	0.9827	likely pathogenic · top 2% in CRYBB1
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -14.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.0069 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,900 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00105% 17/1,614,046 alleles · ultra-rare exomes 15/1,461,810 · genomes 2/152,236 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,207
South Asian	0.0011%	91,084
European (non-Finnish)	0.000169%	590,016

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: CRYBB1
Protein: p.Arg230Ser
Coding: c.688C>A
MANE Select: NM_001887
dbSNP: rs762942964
Type: single nucleotide variant
Location: chr22:26599561 (GRCh38)
Gene constraint: LOEUF 0.789 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.13 · 1 PDB
Residue 230: a UniProt-annotated variant site (in ctrct17; uncertain significance); a β-strand; the beta/gamma crystallin 'greek key' 4 domain

Full CRYBB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 17 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

CRYBB1 p.Ala5Thr Uncertain significance ★ ⚠ same condition
CRYBB1 p.Arg60Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
CRYBB1 p.Arg92Cys Uncertain significance ★ ⚠ same condition
CRYBB1 p.Gly119= Uncertain significance ★ same condition
CRYBB1 p.Thr21= Uncertain significance ★ same condition
CRYBB1 p.Arg182His Uncertain significance ★ ⚠ same type
CRYBB1 p.Phe243Leu Uncertain significance ★ ⚠ same type
CRYBB1 p.Tyr198His Uncertain significance ★ ⚠ same type

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/crybb1-p-arg230ser (accessed [today's date]).

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