Is CRYBB1 p.Arg231His (c.692G>A) pathogenic?

CRYBB1 p.Arg231His (c.692G>A) is classified Uncertain significance in CRYBB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-03). AlphaMissense: likely benign (0.2544); Very rare (popmax 0.00169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CRYBB1 p.Arg231His (c.692G>A)?

CRYBB1 p.Arg231His (c.692G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB1 p.Arg231His (c.692G>A) in the general population?

CRYBB1 p.Arg231His (c.692G>A) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about CRYBB1 p.Arg231His (c.692G>A)?

AlphaMissense predicts likely benign (score 0.2544) — an in-silico prediction, not a clinical call.

CRYBB1 p.Arg231His

c.692G>A · rs745344551 · VCV981118

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2544 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2544	likely benign
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -11.40	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.4	phastCons 0.89
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.0069 · regional, not allelic
Overall
CADD	25.8	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 0.00169% European (non-Finnish) · 20/1,180,044 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00136% 22/1,614,026 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)grpmax	0.00169%	59,002
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Arg231His
Coding: c.692G>A
MANE Select: NM_001886 · reported on NM_001887
dbSNP: rs745344551
Type: single nucleotide variant
Location: chr22:26599557 (GRCh38)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-arg231his (accessed [today's date]).

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