Is CRYAB p.Arg11His (c.32G>A) pathogenic?

CRYAB p.Arg11His (c.32G>A) is classified Conflicting classifications of pathogenicity in CRYAB (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-01). AlphaMissense: ambiguous (0.3502); Very rare (popmax 0.0045%, eas); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Arg11His (c.32G>A)?

CRYAB p.Arg11His (c.32G>A) is associated with dilated cardiomyopathy 1II, cataract 16 multiple types (ClinVar).

How common is CRYAB p.Arg11His (c.32G>A) in the general population?

CRYAB p.Arg11His (c.32G>A) is very rare (popmax 0.0045%, 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.Arg11His (c.32G>A)?

AlphaMissense predicts ambiguous (score 0.3502) — an in-silico prediction, not a clinical call.

CRYAB p.Arg11His

c.32G>A · rs782809283 · VCV870393

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3502 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0045%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
AlphaMissense	0.3502	ambiguous
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -7.47	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.30	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	33.0	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 0.0045% East Asian · 2/44,446 alleles

Filtering AF 0.00181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00158%

Overall 0.00244% 39/1,598,882 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00645%	15,495
East Asiangrpmax	0.0045%	22,223
African / African-American	0.00401%	24,922
European (non-Finnish)	0.00256%	39,100

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg11His
Coding: c.32G>A
MANE Select: NM_001289808
dbSNP: rs782809283
Type: single nucleotide variant
Location: chr11:111911693 (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: cataract 16 multiple types

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.Arg11Gly Uncertain significance ★★ ⚠ 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-arg11his (accessed [today's date]).

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