Is CRYBB2 p.Arg81His (c.242G>A) pathogenic?

CRYBB2 p.Arg81His (c.242G>A) is classified Uncertain significance in CRYBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). AlphaMissense: ambiguous (0.5633); Ultra-rare (popmax 0.0227%, afr); Associated with cataract 3 multiple types.

What condition is associated with CRYBB2 p.Arg81His (c.242G>A)?

CRYBB2 p.Arg81His (c.242G>A) is associated with cataract 3 multiple types (ClinVar).

How common is CRYBB2 p.Arg81His (c.242G>A) in the general population?

CRYBB2 p.Arg81His (c.242G>A) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about CRYBB2 p.Arg81His (c.242G>A)?

AlphaMissense predicts ambiguous (score 0.5633) — an in-silico prediction, not a clinical call.

CRYBB2 p.Arg81His

c.242G>A · rs146763276 · VCV463970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5633 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cataract 3 multiple types

Computational evidence

Protein change
AlphaMissense	0.5633	ambiguous
REVEL	0.683	pathogenic-leaning
SaProt	LLR -9.63	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	31.0	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 0.0227% African / African-American · 17/75,028 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00229% 37/1,614,118 alleles · ultra-rare exomes 22/1,461,880 · genomes 15/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,413
Middle Eastern	0.0165%	6,062
East Asian	0.00223%	44,874
South Asian	0.0022%	45,537
European (non-Finnish)	0.00136%	73,751

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: CRYBB2
Protein: p.Arg81His
Coding: c.242G>A
MANE Select: NM_000496
dbSNP: rs146763276
Type: single nucleotide variant
Location: chr22:25227921 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 81: the beta/gamma crystallin 'greek key' 2 domain

Full CRYBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 3 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYBB2 p.Arg188Cys Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 p.Arg188His Pathogenic ★★ same condition
CRYBB2 p.Gln155Ter Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 p.Gly119Arg Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 p.Arg160Pro Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Gly57Glu Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Gly61Ser Uncertain significance ★★ ⚠ same condition
CRYBB2 c.449+9G>A Benign ★★ 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/crybb2-p-arg81his (accessed [today's date]).

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