Is CRYBB1 p.Arg92Cys (c.274C>T) pathogenic?

CRYBB1 p.Arg92Cys (c.274C>T) is classified Uncertain significance in CRYBB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-02). AlphaMissense: likely benign (0.1778); Very rare (popmax 0.00935%, afr); Associated with cataract 17 multiple types.

What condition is associated with CRYBB1 p.Arg92Cys (c.274C>T)?

CRYBB1 p.Arg92Cys (c.274C>T) is associated with cataract 17 multiple types (ClinVar).

How common is CRYBB1 p.Arg92Cys (c.274C>T) in the general population?

CRYBB1 p.Arg92Cys (c.274C>T) is very rare (popmax 0.00935%, 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 CRYBB1 p.Arg92Cys (c.274C>T)?

AlphaMissense predicts likely benign (score 0.1778) — an in-silico prediction, not a clinical call.

CRYBB1 p.Arg92Cys

c.274C>T · rs374800624 · VCV902687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 17 multiple types

Computational evidence

Protein change
AlphaMissense	0.1778	likely benign
REVEL	0.729	pathogenic-leaning
SaProt	LLR -6.79	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -2.8, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,848 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00229% 37/1,613,306 alleles · very rare exomes 32/1,461,362 · genomes 5/151,944 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,693
European (non-Finnish)	0.00229%	43,693
East Asian	0.00223%	44,864
Admixed American	0.00167%	59,974
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Arg92Cys
Coding: c.274C>T
MANE Select: NM_001887
dbSNP: rs374800624
Type: single nucleotide variant
Location: chr22:26612097 (GRCh38)
Gene constraint: LOEUF 0.789 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.13 · 1 PDB
Residue 92: the beta/gamma crystallin 'greek key' 1 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.Arg230Ser Uncertain significance ★ ⚠ same condition
CRYBB1 p.Arg60Thr Conflicting classifications of pathogenicity ★ ⚠ 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-arg92cys (accessed [today's date]).

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