Is CRYAB p.Pro58= (c.174C>A) pathogenic?

CRYAB p.Pro58= (c.174C>A) is classified Likely benign in CRYAB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-01). Ultra-rare (popmax 0.0469%, amr); Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.Pro58= (c.174C>A)?

CRYAB p.Pro58= (c.174C>A) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Pro58= (c.174C>A) in the general population?

CRYAB p.Pro58= (c.174C>A) is ultra-rare (popmax 0.0469%, amr) (gnomAD).

CRYAB p.Pro58=

c.174C>A · rs782151852 · VCV696164

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0469%, amr)

Conditions

Cardiovascular phenotype

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 2	GERP -4.3, phastCons 1
Overall
CADD	8.282	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0469% Admixed American · 28/59,742 alleles

Filtering AF 0.0333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0287%

Overall 0.0018% 29/1,612,362 alleles · ultra-rare exomes 26/1,460,210 · genomes 3/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0469%	2,134
European (non-Finnish)	8.48e-05%	1,179,549

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.Pro58=
Coding: c.174C>A
MANE Select: NM_001289808
dbSNP: rs782151852
Type: single nucleotide variant
Location: chr11:111911551 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 58: the shsp domain

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.Pro58His Uncertain significance ★ ⚠ same residue
CRYAB p.Pro58Leu Uncertain significance ★ ⚠ same residue
CRYAB p.Pro58Ala 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-pro58 (accessed [today's date]).

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