Is CRYAB p.Ser115fs (c.343del) pathogenic?

CRYAB p.Ser115fs (c.343del) is classified Conflicting classifications of pathogenicity in CRYAB (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). Very rare (popmax 0.00401%, afr); Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.Ser115fs (c.343del)?

CRYAB p.Ser115fs (c.343del) is associated with Cardiovascular phenotype, myofibrillar myopathy 2, cataract 16 multiple types (ClinVar).

How common is CRYAB p.Ser115fs (c.343del) in the general population?

CRYAB p.Ser115fs (c.343del) is very rare (popmax 0.00401%, afr) (gnomAD).

CRYAB p.Ser115fs

c.343del · rs281865142 · VCV38963

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,880 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000991% 16/1,613,966 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,960
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	0.000932%	107,275

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.Ser115fs
Coding: c.343del
MANE Select: NM_001289808
dbSNP: rs281865142
Type: Deletion
Location: chr11:111908949 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 2 cataract 16 multiple types fatal infantile hypertonic myofibrillar myopathy dilated cardiomyopathy 1II

Similar variants

CRYAB p.Ser115= Conflicting classifications of pathogenicity ★ same residue
CRYAB p.Lys82_His83delinsAsn Uncertain significance ★★ same condition
CRYAB p.Ala172fs Pathogenic ★ same condition
CRYAB p.Arg11fs Pathogenic ★ same condition
CRYAB p.Leu49fs Pathogenic ★ same condition
CRYAB p.Ser21fs Pathogenic ★ same condition
CRYAB p.Ala126fs Uncertain significance ★ same condition
CRYAB p.Arg50_Phe54del 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-ser115fs (accessed [today's date]).

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