Is CRYAB p.Arg74= (c.220A>C) pathogenic?

CRYAB p.Arg74= (c.220A>C) is classified Likely benign in CRYAB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). Very rare (popmax 0.00407%, nfe); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Arg74= (c.220A>C)?

CRYAB p.Arg74= (c.220A>C) is associated with dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Arg74= (c.220A>C) in the general population?

CRYAB p.Arg74= (c.220A>C) is very rare (popmax 0.00407%, 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.

CRYAB p.Arg74=

c.220A>C · rs781913291 · VCV1625383

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00407%, nfe)

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Overall
CADD	13.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00407% European (non-Finnish) · 48/1,180,026 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00335% 49/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00407%	24,584
Remaining individualsnot grpmax-eligible	0.0016%	62,512

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.Arg74=
Coding: c.220A>C
MANE Select: NM_001289808
dbSNP: rs781913291
Type: single nucleotide variant
Location: chr11:111910431 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 74: the shsp domain; a β-strand

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.Arg74Ser Uncertain significance ★★ same residue
CRYAB p.Arg74Gly 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-arg74 (accessed [today's date]).

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