Is CRYAB p.Arg12Cys (c.34C>T) pathogenic?

CRYAB p.Arg12Cys (c.34C>T) is classified Conflicting classifications of pathogenicity in CRYAB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-11). AlphaMissense: likely pathogenic (0.8198); Ultra-rare (popmax 0.0113%, sas); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Arg12Cys (c.34C>T)?

CRYAB p.Arg12Cys (c.34C>T) is associated with dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Arg12Cys (c.34C>T) in the general population?

CRYAB p.Arg12Cys (c.34C>T) is ultra-rare (popmax 0.0113%, sas) (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.Arg12Cys (c.34C>T)?

AlphaMissense predicts likely pathogenic (score 0.8198) — an in-silico prediction, not a clinical call.

CRYAB p.Arg12Cys

c.34C>T · rs375933774 · VCV1069484

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8198 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
AlphaMissense	0.8198	likely pathogenic
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -11.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	34.0	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 0.0113% South Asian · 10/88,592 alleles

Filtering AF 0.00609% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00464%

Overall 0.00106% 17/1,599,392 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0113%	8,859
African / African-American	0.00267%	37,451
European (non-Finnish)	0.000426%	234,650

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.Arg12Cys
Coding: c.34C>T
MANE Select: NM_001289808
dbSNP: rs375933774
Type: single nucleotide variant
Location: chr11:111911691 (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.Arg12Leu Uncertain significance ★★ ⚠ same residue
CRYAB p.Arg12His Uncertain significance ★ ⚠ same residue
CRYAB p.Arg12Gly 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-arg12cys (accessed [today's date]).

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