Is CRYAB p.Pro125= (c.375A>C) pathogenic?

CRYAB p.Pro125= (c.375A>C) is classified Conflicting classifications of pathogenicity in CRYAB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-28). Very rare (popmax 8.47e-05%, nfe); Associated with fatal infantile hypertonic myofibrillar myopathy.

What condition is associated with CRYAB p.Pro125= (c.375A>C)?

CRYAB p.Pro125= (c.375A>C) is associated with fatal infantile hypertonic myofibrillar myopathy, cataract 16 multiple types, dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Pro125= (c.375A>C) in the general population?

CRYAB p.Pro125= (c.375A>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CRYAB p.Pro125=

Q: How is Fatal infantile hypertonic myofibrillar myopathy inherited?

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

c.375A>C · rs886047687 · VCV302431

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 8.47e-05%, nfe)

Conditions

fatal infantile hypertonic myofibrillar myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.014	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.25	GERP -3.9, phastCons 0.47
Overall
CADD	8.876	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.2e-05% 1/1,614,116 alleles · very rare exomes 1/1,461,880 · genomes 0/152,236 · 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.Pro125=
Coding: c.375A>C
MANE Select: NM_001289808
dbSNP: rs886047687
Type: single nucleotide variant
Location: chr11:111908917 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 125: the shsp domain; a turn

Full CRYAB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

fatal infantile hypertonic myofibrillar myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cataract 16 multiple types dilated cardiomyopathy 1II

For Fatal infantile hypertonic myofibrillar myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CRYAB p.Pro125Ser Uncertain significance ★★ ⚠ same residue
CRYAB p.Pro125Ala 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
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-pro125 (accessed [today's date]).

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