Is CRYAB p.Leu23= (c.69C>G) pathogenic?

CRYAB p.Leu23= (c.69C>G) is classified Conflicting classifications of pathogenicity in CRYAB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-17). Ultra-rare (popmax 0.0495%, mid); Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.Leu23= (c.69C>G)?

CRYAB p.Leu23= (c.69C>G) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Leu23= (c.69C>G) in the general population?

CRYAB p.Leu23= (c.69C>G) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

CRYAB p.Leu23=

c.69C>G · rs1965462205 · VCV3221864

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

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 8.6	GERP 2.3, phastCons 1
Overall
CADD	12.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,058 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.000274% 4/1,457,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
African / African-American	0.00133%	75,014

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.Leu23=
Coding: c.69C>G
MANE Select: NM_001289808
dbSNP: rs1965462205
Type: single nucleotide variant
Location: chr11:111911656 (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.Leu23Pro 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
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-leu23 (accessed [today's date]).

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