Is CRYBA2 p.Arg96Trp (c.286C>T) pathogenic?

CRYBA2 p.Arg96Trp (c.286C>T) is classified Uncertain significance in CRYBA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-09). AlphaMissense: ambiguous (0.4978); Ultra-rare (popmax 0.0528%, sas).

How common is CRYBA2 p.Arg96Trp (c.286C>T) in the general population?

CRYBA2 p.Arg96Trp (c.286C>T) is ultra-rare (popmax 0.0528%, sas) (gnomAD).

What do computational predictors say about CRYBA2 p.Arg96Trp (c.286C>T)?

AlphaMissense predicts ambiguous (score 0.4978) — an in-silico prediction, not a clinical call.

CRYBA2 p.Arg96Trp

c.286C>T · rs576572225 · VCV1050665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0528%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4978	ambiguous
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -15.13	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -0.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,921 bp · p 0.71 · regional, not allelic
Overall
CADD	25.4	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 0.0528% South Asian · 48/90,994 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.00812% 131/1,613,222 alleles · ultra-rare exomes 114/1,460,842 · genomes 17/152,380 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0528%	1,896
African / African-American	0.0107%	9,382
European (non-Finnish)	0.00593%	16,853
East Asian	0.00446%	22,427
Admixed American	0.00333%	29,988
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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.Arg96Trp
Coding: c.286C>T
MANE Select: NM_057093
dbSNP: rs576572225
Type: single nucleotide variant
Location: chr2:218992119 (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.Arg96Gln 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-arg96trp (accessed [today's date]).

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