Is CRYAB p.Lys166Ter (c.496A>T) pathogenic?

CRYAB p.Lys166Ter (c.496A>T) is classified Uncertain significance in CRYAB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). Ultra-rare (popmax 0.038%, mid); Associated with dilated cardiomyopathy 1II.

What condition is associated with CRYAB p.Lys166Ter (c.496A>T)?

CRYAB p.Lys166Ter (c.496A>T) is associated with dilated cardiomyopathy 1II (ClinVar).

How common is CRYAB p.Lys166Ter (c.496A>T) in the general population?

CRYAB p.Lys166Ter (c.496A>T) is ultra-rare (popmax 0.038%, mid) (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.Lys166Ter

c.496A>T · rs2497874732 · VCV2421848

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.038%, mid)

Conditions

dilated cardiomyopathy 1II

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	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
REVEL	0.704	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.27	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 6.1	GERP 2.3, phastCons 1
Overall
CADD	37.0	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 0.038% Middle Eastern · 2/5,258 alleles

Filtering AF 0.00674% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00282%

Overall 0.000274% 4/1,460,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.038%	2,629
European (non-Finnish)	0.000169%	590,005

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.Lys166Ter
Coding: c.496A>T
MANE Select: NM_001289808
dbSNP: rs2497874732
Type: single nucleotide variant
Location: chr11:111908796 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 166: a modified residue (n6-acetyllysine); the 'disordered' region

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.Lys166= 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
CRYAB p.Ala4Thr 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-lys166ter (accessed [today's date]).

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