Is CRYAB p.Ser138= (c.414A>G) pathogenic?

CRYAB p.Ser138= (c.414A>G) is classified Likely benign in CRYAB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-09). Very rare (popmax 0.000339%, nfe); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Ser138= (c.414A>G)?

CRYAB p.Ser138= (c.414A>G) is associated with dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Ser138= (c.414A>G) in the general population?

CRYAB p.Ser138= (c.414A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CRYAB p.Ser138=

c.414A>G · rs2497875184 · VCV1897741

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.067	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.9	GERP -4.7
Overall
CADD	6.109	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,020 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,854 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.Ser138=
Coding: c.414A>G
MANE Select: NM_001289808
dbSNP: rs2497875184
Type: single nucleotide variant
Location: chr11:111908878 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 138: the shsp domain

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

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 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 p.Ala168Gly Uncertain significance ★★ ⚠ same condition
CRYAB p.Ala171Thr Uncertain significance ★★ ⚠ same condition
CRYAB p.Ala4Thr Uncertain significance ★★ ⚠ same condition
CRYAB p.Arg107Cys 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-ser138 (accessed [today's date]).

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