Is CRYBA2 p.Arg96Gln (c.287G>A) pathogenic?

CRYBA2 p.Arg96Gln (c.287G>A) is classified Uncertain significance in CRYBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.2705); Ultra-rare (popmax 0.0165%, mid).

How common is CRYBA2 p.Arg96Gln (c.287G>A) in the general population?

CRYBA2 p.Arg96Gln (c.287G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CRYBA2 p.Arg96Gln (c.287G>A)?

AlphaMissense predicts likely benign (score 0.2705) — an in-silico prediction, not a clinical call.

CRYBA2 p.Arg96Gln

c.287G>A · rs772123899 · VCV3077706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2705	likely benign
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -13.03	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,921 bp · p 0.71 · regional, not allelic
Overall
CADD	26.5	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 0.0165% Middle Eastern · 1/6,044 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0013% 19/1,460,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,044
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)	0.00136%	73,731
African / African-American	0.00133%	75,038

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: CRYBA2
Protein: p.Arg96Gln
Coding: c.287G>A
MANE Select: NM_057093
dbSNP: rs772123899
Type: single nucleotide variant
Location: chr2:218992118 (GRCh38)
Gene constraint: LOEUF 1.372 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12
Residue 96: the beta/gamma crystallin 'greek key' 2 domain

Full CRYBA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRYBA2 p.Arg96Trp Uncertain significance ★ ⚠ same residue
CRYBA2 p.Ala80Thr Uncertain significance ★★ ⚠ same type
CRYBA2 c.303+127A>G Benign ★★ same type
CRYBA2 c.304-16T>C Benign ★★ same type
CRYBA2 c.303+5G>A Uncertain significance ★ same type
CRYBA2 c.446+1G>A Uncertain significance ★ same type
CRYBA2 p.Ala10Pro Uncertain significance ★ ⚠ same type
CRYBA2 p.Ala34Glu 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/cryba2-p-arg96gln (accessed [today's date]).

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