Is CRYAB p.Arg11Gly (c.31C>G) pathogenic?

CRYAB p.Arg11Gly (c.31C>G) is classified Uncertain significance in CRYAB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.5342); Very rare (popmax 0.000768%, nfe); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Arg11Gly (c.31C>G)?

CRYAB p.Arg11Gly (c.31C>G) is associated with dilated cardiomyopathy 1II, myofibrillar myopathy 2, cataract 16 multiple types (ClinVar).

How common is CRYAB p.Arg11Gly (c.31C>G) in the general population?

CRYAB p.Arg11Gly (c.31C>G) is very rare (popmax 0.000768%, nfe) (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.Arg11Gly (c.31C>G)?

AlphaMissense predicts ambiguous (score 0.5342) — an in-silico prediction, not a clinical call.

CRYAB p.Arg11Gly

c.31C>G · rs781902168 · VCV964348

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5342 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000768%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
AlphaMissense	0.5342	ambiguous
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -7.81	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 1.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	29.5	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 0.000768% European (non-Finnish) · 9/1,172,126 alleles

Filtering AF 0.000361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000262%

Overall 0.000563% 9/1,597,162 alleles · very rare

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.Arg11Gly
Coding: c.31C>G
MANE Select: NM_001289808
dbSNP: rs781902168
Type: single nucleotide variant
Location: chr11:111911694 (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: myofibrillar myopathy 2 cataract 16 multiple types fatal infantile hypertonic myofibrillar myopathy

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.Arg11Cys Uncertain significance ★★ ⚠ same residue
CRYAB p.Arg11His Conflicting classifications of pathogenicity ★ ⚠ same residue
CRYAB p.Arg11Pro Uncertain significance ★ ⚠ same residue
CRYAB p.Arg11= Likely benign ★ same residue
CRYAB p.Arg11fs Pathogenic ★ 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

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-arg11gly (accessed [today's date]).

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