Is CRYAB p.Ser21fs (c.60del) pathogenic?

CRYAB p.Ser21fs (c.60del) is classified Pathogenic in CRYAB (ClinVar, Single submitter, 3 submitters; last evaluated 2025-04-18). Absent from gnomAD v4.1; Associated with myofibrillar myopathy 2.

What condition is associated with CRYAB p.Ser21fs (c.60del)?

CRYAB p.Ser21fs (c.60del) is associated with myofibrillar myopathy 2 (ClinVar).

How common is CRYAB p.Ser21fs (c.60del) in the general population?

CRYAB p.Ser21fs (c.60del) is absent from gnomAD v4.1 (gnomAD).

How is Alpha-B crystallin-related late-onset myopathy inherited?

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

CRYAB p.Ser21fs

c.60del · rs281865141 · VCV29669

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,608,458)

Conditions

myofibrillar myopathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,608,458). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CRYAB
Protein: p.Ser21fs
Coding: c.60del
MANE Select: NM_001289808
dbSNP: rs281865141
Type: Deletion
Location: chr11:111911665 (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

myofibrillar myopathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alpha-B crystallin-related late-onset myopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CRYAB p.Ala172fs Pathogenic ★ same condition
CRYAB p.Lys174fs Conflicting classifications of pathogenicity ★ same condition
CRYAB p.Pro155fs Uncertain significance ★ same condition
CRYAB p.Ser115fs Conflicting classifications of pathogenicity ★ same condition
HSPB2 p.Pro21Leu Uncertain significance ★ ⚠ same residue
CRYAB p.Ala168Gly Uncertain significance ★★ ⚠ same condition
CRYAB p.Arg107Cys Uncertain significance ★★ ⚠ same condition
CRYAB p.Arg11Gly 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-ser21fs (accessed [today's date]).

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