Is CRYBA2 p.Arg25Ser (c.73C>A) pathogenic?

CRYBA2 p.Arg25Ser (c.73C>A) is classified Uncertain significance in CRYBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: ambiguous (0.3789); Very rare (popmax 0.00195%, nfe).

How common is CRYBA2 p.Arg25Ser (c.73C>A) in the general population?

CRYBA2 p.Arg25Ser (c.73C>A) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about CRYBA2 p.Arg25Ser (c.73C>A)?

AlphaMissense predicts ambiguous (score 0.3789) — an in-silico prediction, not a clinical call.

CRYBA2 p.Arg25Ser

c.73C>A · VCV3269653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3789	ambiguous
REVEL	0.605	indeterminate
SaProt	LLR -5.44	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,921 bp · p 0.71 · regional, not allelic
Overall
CADD	26.8	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 0.00195% European (non-Finnish) · 23/1,179,408 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00143% 23/1,611,794 alleles · very rare

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.Arg25Ser
Coding: c.73C>A
MANE Select: NM_057093
Type: single nucleotide variant
Location: chr2:218993104 (GRCh38)
Gene constraint: LOEUF 1.372 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12
Residue 25: the beta/gamma crystallin 'greek key' 1 domain

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

Similar variants

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
CRYBA2 p.Ala6Ser 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-arg25ser (accessed [today's date]).

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