Is CRYAB p.Phe14Ser (c.41T>C) pathogenic?

CRYAB p.Phe14Ser (c.41T>C) is classified Uncertain significance in CRYAB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-14). AlphaMissense: ambiguous (0.4254); Very rare (popmax 8.51e-05%, nfe); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Phe14Ser (c.41T>C)?

CRYAB p.Phe14Ser (c.41T>C) is associated with dilated cardiomyopathy 1II, myofibrillar myopathy 2 (ClinVar).

How common is CRYAB p.Phe14Ser (c.41T>C) in the general population?

CRYAB p.Phe14Ser (c.41T>C) is very rare (popmax 8.51e-05%, 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.

What do computational predictors say about CRYAB p.Phe14Ser (c.41T>C)?

AlphaMissense predicts ambiguous (score 0.4254) — an in-silico prediction, not a clinical call.

CRYAB p.Phe14Ser

c.41T>C · rs1555165594 · VCV1390439

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4254 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
AlphaMissense	0.4254	ambiguous
REVEL	0.642	indeterminate
SaProt	LLR -4.92	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	25.2	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 8.51e-05% European (non-Finnish) · 1/1,175,528 alleles

Overall 6.23e-05% 1/1,603,886 alleles · very rare exomes 1/1,451,702 · genomes 0/152,184 · 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.Phe14Ser
Coding: c.41T>C
MANE Select: NM_001289808
dbSNP: rs1555165594
Type: single nucleotide variant
Location: chr11:111911684 (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

dilated cardiomyopathy 1II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 2

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.Phe14Val Uncertain significance ★ ⚠ same residue
CRYAB p.Phe14= Likely benign ★ 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
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-phe14ser (accessed [today's date]).

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