Is CRYBB1 p.Arg92His (c.275G>A) pathogenic?

CRYBB1 p.Arg92His (c.275G>A) is classified Uncertain significance in CRYBB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-29). AlphaMissense: likely benign (0.1671); Rare (popmax 0.107%, eas); Associated with cataract 17 multiple types.

What condition is associated with CRYBB1 p.Arg92His (c.275G>A)?

CRYBB1 p.Arg92His (c.275G>A) is associated with cataract 17 multiple types (ClinVar).

How common is CRYBB1 p.Arg92His (c.275G>A) in the general population?

CRYBB1 p.Arg92His (c.275G>A) is rare (popmax 0.107%, 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.Arg92His (c.275G>A)?

AlphaMissense predicts likely benign (score 0.1671) — an in-silico prediction, not a clinical call.

CRYBB1 p.Arg92His

c.275G>A · rs750427170 · VCV341048

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1671 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cataract 17 multiple types

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1671	likely benign
REVEL	0.408	indeterminate
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.0069 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.107% East Asian · 48/44,854 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0744%

Overall 0.00998% 161/1,613,370 alleles · rare exomes 150/1,461,202 · genomes 11/152,168 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.176%	569
East Asiangrpmax	0.107%	934
Remaining individualsnot grpmax-eligible	0.0128%	7,810
Admixed American	0.005%	20,002
European (non-Finnish)	0.00398%	25,098
South Asian	0.0022%	45,535
Finnishnot grpmax-eligible	0.00157%	63,798

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg92His
Coding: c.275G>A
MANE Select: NM_001887
dbSNP: rs750427170
Type: single nucleotide variant
Location: chr22:26612096 (GRCh38)

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

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-arg92his (accessed [today's date]).

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