Is CRYAB p.Arg69Ser (c.205C>A) pathogenic?

CRYAB p.Arg69Ser (c.205C>A) is classified Uncertain significance in CRYAB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-16). AlphaMissense: likely pathogenic (0.7292); Very rare (popmax 0.004%, afr); Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.Arg69Ser (c.205C>A)?

CRYAB p.Arg69Ser (c.205C>A) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Arg69Ser (c.205C>A) in the general population?

CRYAB p.Arg69Ser (c.205C>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CRYAB p.Arg69Ser (c.205C>A)?

AlphaMissense predicts likely pathogenic (score 0.7292) — an in-silico prediction, not a clinical call.

CRYAB p.Arg69Ser

c.205C>A · rs139750142 · VCV1025732

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7292 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7292	likely pathogenic
REVEL	0.622	indeterminate
SaProt	LLR -8.61	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	29.1	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 0.004% African / African-American · 3/74,916 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,036 alleles · very rare exomes 2/1,461,860 · genomes 1/152,176 · joint denominator

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.Arg69Ser
Coding: c.205C>A
MANE Select: NM_001289808
dbSNP: rs139750142
Type: single nucleotide variant
Location: chr11:111910446 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 69: the shsp domain; a UniProt-annotated variant site (in ctrct16; uncertain significance); a β-strand

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.Arg69Cys Uncertain significance ★★ ⚠ same residue
CRYAB p.Arg69His Uncertain significance ★★ ⚠ same residue
CRYAB p.Arg69Leu 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 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-arg69ser (accessed [today's date]).

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