Is CRYAB p.Pro8Ser (c.22C>T) pathogenic?

CRYAB p.Pro8Ser (c.22C>T) is classified Uncertain significance in CRYAB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-12). AlphaMissense: ambiguous (0.5275); Very rare (popmax 0.00226%, eas); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Pro8Ser (c.22C>T)?

CRYAB p.Pro8Ser (c.22C>T) is associated with dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Pro8Ser (c.22C>T) in the general population?

CRYAB p.Pro8Ser (c.22C>T) is very rare (popmax 0.00226%, 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.Pro8Ser (c.22C>T)?

AlphaMissense predicts ambiguous (score 0.5275) — an in-silico prediction, not a clinical call.

CRYAB p.Pro8Ser

c.22C>T · rs782654756 · VCV222530

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5275 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
AlphaMissense	0.5275	ambiguous
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -8.29	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	26.0	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 0.00226% East Asian · 1/44,178 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000208% 3/1,439,610 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00226%	44,178
European (non-Finnish)	0.000171%	584,604

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.Pro8Ser
Coding: c.22C>T
MANE Select: NM_001289808
dbSNP: rs782654756
Type: single nucleotide variant
Location: chr11:111911703 (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

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.Pro8= Likely benign ★ same residue
HSPB2 p.His8Arg 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
CRYAB p.Ala171Thr 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-pro8ser (accessed [today's date]).

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