Is CRYBA2 p.Gly181Ser (c.541G>A) pathogenic?

CRYBA2 p.Gly181Ser (c.541G>A) is classified Uncertain significance in CRYBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-07). AlphaMissense: likely benign (0.1473); Ultra-rare (popmax 0.0165%, mid).

How common is CRYBA2 p.Gly181Ser (c.541G>A) in the general population?

CRYBA2 p.Gly181Ser (c.541G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CRYBA2 p.Gly181Ser (c.541G>A)?

AlphaMissense predicts likely benign (score 0.1473) — an in-silico prediction, not a clinical call.

CRYBA2 p.Gly181Ser

c.541G>A · rs748194398 · VCV2510735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1473 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1473	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.79	GERP 1.1, phastCons 0.22
Regional constraint	o/e 1.02	unconstrained · MANE · 2,921 bp · p 0.71 · regional, not allelic
Overall
CADD	18.49	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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 · 1/6,058 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00116% 17/1,461,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Finnishnot grpmax-eligible	0.00156%	64,038
African / African-American	0.00133%	75,028
European (non-Finnish)	0.000847%	118,001

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.Gly181Ser
Coding: c.541G>A
MANE Select: NM_057093
dbSNP: rs748194398
Type: single nucleotide variant
Location: chr2:218990305 (GRCh38)
Gene constraint: LOEUF 1.372 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12
Residue 181: the beta/gamma crystallin 'greek key' 4 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-gly181ser (accessed [today's date]).

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