Is CRYAB p.Ala4Thr (c.10G>A) pathogenic?

CRYAB p.Ala4Thr (c.10G>A) is classified Uncertain significance in CRYAB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-09). AlphaMissense: likely benign (0.1136); Very rare (popmax 0.00228%, eas); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Ala4Thr (c.10G>A)?

CRYAB p.Ala4Thr (c.10G>A) is associated with dilated cardiomyopathy 1II, cataract 16 multiple types (ClinVar).

How common is CRYAB p.Ala4Thr (c.10G>A) in the general population?

CRYAB p.Ala4Thr (c.10G>A) is very rare (popmax 0.00228%, eas) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CRYAB p.Ala4Thr (c.10G>A)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

CRYAB p.Ala4Thr

c.10G>A · rs1264081192 · VCV931448

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00228%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -7.14	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	22.0	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 0.00228% East Asian · 1/43,888 alleles

Filtering AF 0.000434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000316%

Overall 0.000757% 12/1,584,966 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00228%	43,888
Finnishnot grpmax-eligible	0.00162%	61,844
European (non-Finnish)	0.000858%	116,555

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: CRYAB
Protein: p.Ala4Thr
Coding: c.10G>A
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

dilated cardiomyopathy 1II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cataract 16 multiple types

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CRYAB p.Ala4= Likely benign ★ same residue
CRYAB p.Ala4Ser Uncertain significance ★ ⚠ same residue
HSPB2 p.Arg4Ser Uncertain significance ★ ⚠ same residue
CRYAB c.324+4T>A Uncertain significance ★★ same condition
CRYAB c.324+5G>T Uncertain significance ★★ same condition
CRYAB c.325-1G>A Uncertain significance ★★ same condition
CRYAB c.325-2A>G Uncertain significance ★★ same condition
CRYAB p.Ala168Gly 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-ala4thr (accessed [today's date]).

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