Is CRYAB p.Ala4Ser (c.10G>T) pathogenic?

CRYAB p.Ala4Ser (c.10G>T) is classified Uncertain significance in CRYAB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-27). AlphaMissense: likely benign (0.1327); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.Ala4Ser (c.10G>T)?

CRYAB p.Ala4Ser (c.10G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is CRYAB p.Ala4Ser (c.10G>T) in the general population?

CRYAB p.Ala4Ser (c.10G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYAB p.Ala4Ser (c.10G>T)?

AlphaMissense predicts likely benign (score 0.1327) — an in-silico prediction, not a clinical call.

CRYAB p.Ala4Ser

c.10G>T · rs1264081192 · VCV3221860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1327 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,585,086)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1327	likely benign
REVEL	0.375	indeterminate
SaProt	LLR -6.00	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 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	21.7	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

No allele count reported in gnomAD v4.1 (AN 1,585,086). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CRYAB
Protein: p.Ala4Ser
Coding: c.10G>T
MANE Select: NM_001289808
dbSNP: rs1264081192
Type: single nucleotide variant
Location: chr11:111911715 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYAB p.Ala4Thr Uncertain significance ★★ ⚠ same residue
HSPB2 p.Arg4Ser Uncertain significance ★ ⚠ same residue
CRYAB p.Ala4= Likely benign ★ same residue
CRYAB c.324+4T>A Uncertain significance ★★ same condition
CRYAB c.325-2A>G Uncertain significance ★★ same condition
CRYAB c.-5C>T Uncertain significance ★★ same condition
CRYAB p.Ala171Thr Uncertain significance ★★ ⚠ same condition
CRYAB p.Arg11Cys Uncertain significance ★★ ⚠ 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/cryab-p-ala4ser (accessed [today's date]).

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