Is CRYAB p.Pro39Gln (c.116C>A) pathogenic?

CRYAB p.Pro39Gln (c.116C>A) is classified Uncertain significance in CRYAB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-03). AlphaMissense: likely benign (0.1672); Absent from gnomAD v4.1; Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Pro39Gln (c.116C>A)?

CRYAB p.Pro39Gln (c.116C>A) is associated with dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Pro39Gln (c.116C>A) in the general population?

CRYAB p.Pro39Gln (c.116C>A) is absent from gnomAD v4.1 (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.Pro39Gln (c.116C>A)?

AlphaMissense predicts likely benign (score 0.1672) — an in-silico prediction, not a clinical call.

CRYAB p.Pro39Gln

c.116C>A · rs149787233 · VCV566247

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1672 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
AlphaMissense	0.1672	likely benign
REVEL	0.715	pathogenic-leaning
SaProt	LLR -8.68	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	25.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CRYAB
Protein: p.Pro39Gln
Coding: c.116C>A
MANE Select: NM_001289808
dbSNP: rs149787233
Type: single nucleotide variant
Location: chr11:111911609 (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.Pro39Ala Uncertain significance ★★ ⚠ same residue
CRYAB p.Pro39Ser Uncertain significance ★★ ⚠ same residue
CRYAB p.Pro39= Likely benign ★★ same residue
CRYAB p.Pro39Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro39gln (accessed [today's date]).

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