Is CRYAB p.Ser115= (c.345C>T) pathogenic?

CRYAB p.Ser115= (c.345C>T) is classified Conflicting classifications of pathogenicity in CRYAB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-09). Very rare (popmax 0.0011%, sas); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Ser115= (c.345C>T)?

CRYAB p.Ser115= (c.345C>T) is associated with dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Ser115= (c.345C>T) in the general population?

CRYAB p.Ser115= (c.345C>T) is very rare (popmax 0.0011%, sas) (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.Ser115=

c.345C>T · rs782067034 · VCV1731612

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Pangolin	Δ0.23	gain · loss 0.23 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.9	GERP -0.84, phastCons 1
Overall
CADD	15.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,964 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	0.000254%	393,340

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.Ser115=
Coding: c.345C>T
MANE Select: NM_001289808
dbSNP: rs782067034
Type: single nucleotide variant
Location: chr11:111908947 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 115: the shsp domain; a β-strand

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 p.Ser115fs Conflicting classifications of pathogenicity ★ same residue
HSPB2 p.Arg115Gln Uncertain significance ★ ⚠ same residue
HSPB2 p.Arg115Pro 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 p.Ala168Gly 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-ser115 (accessed [today's date]).

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