Is CRYAB p.His7Arg (c.20A>G) pathogenic?

CRYAB p.His7Arg (c.20A>G) is classified Uncertain significance in CRYAB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-19). AlphaMissense: likely benign (0.3087); Very rare (popmax 0.000942%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.His7Arg (c.20A>G)?

CRYAB p.His7Arg (c.20A>G) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.His7Arg (c.20A>G) in the general population?

CRYAB p.His7Arg (c.20A>G) is very rare (popmax 0.000942%, nfe) (gnomAD).

What do computational predictors say about CRYAB p.His7Arg (c.20A>G)?

AlphaMissense predicts likely benign (score 0.3087) — an in-silico prediction, not a clinical call.

CRYAB p.His7Arg

c.20A>G · rs1467726434 · VCV1515526

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000942%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3087	likely benign
REVEL	0.655	pathogenic-leaning
SaProt	LLR -6.39	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 6.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	24.8	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 0.000942% European (non-Finnish) · 11/1,167,788 alleles

Filtering AF 0.000505% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000369%

Overall 0.000692% 11/1,588,708 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.His7Arg
Coding: c.20A>G
MANE Select: NM_001289808
dbSNP: rs1467726434
Type: single nucleotide variant
Location: chr11:111911705 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1II

Similar variants

CRYAB p.His7Tyr Uncertain significance ★★ ⚠ same residue
CRYAB p.His7Gln Uncertain significance ★ ⚠ same residue
CRYAB p.His7= Likely benign ★ 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 c.-5C>T 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-his7arg (accessed [today's date]).

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