Is TTN p.Lys8933fs (c.26798_26799del) pathogenic?

TTN p.Lys8933fs (c.2679826799del) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-11). Very rare (popmax 8.7e-05%, nfe); Associated with dilated cardiomyopathy 1G.

What condition is associated with TTN p.Lys8933fs (c.26798_26799del)?

TTN p.Lys8933fs (c.26798_26799del) is associated with dilated cardiomyopathy 1G, cardiomyopathy, autosomal recessive limb-girdle muscular dystrophy type 2J (ClinVar).

How common is TTN p.Lys8933fs (c.26798_26799del) in the general population?

TTN p.Lys8933fs (c.26798_26799del) is very rare (popmax 8.7e-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.

TTN p.Lys8933fs

c.26798_26799del · rs2076941998 · VCV1329126

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.7e-05%, nfe)

Conditions

dilated cardiomyopathy 1G

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 93 of 363
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 2.8, 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 8.7e-05% European (non-Finnish) · 1/1,149,842 alleles

Overall 0.000658% 1/151,902 alleles · very rare

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: TTN
Protein: p.Lys8933fs
Coding: c.26798_26799del
MANE Select: NM_001267550
dbSNP: rs2076941998
Type: Deletion
Location: chr2:178713335 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 8933: a disulfide bond; the ig-like 72 domain

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

Disease context

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

Also linked: cardiomyopathy autosomal recessive limb-girdle muscular dystrophy type 2J

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

TTN c.32888-1del Likely pathogenic ★★ same condition
TTN c.49648+2del Pathogenic ★★ same condition
TTN c.80003_80028+4del Likely pathogenic ★★ same condition
TTN c.86822-1del Likely pathogenic ★★ same condition
TTN p.Ala14213fs Likely pathogenic ★★ same condition
TTN p.Ala18013fs Likely pathogenic ★★ same condition
TTN p.Ala18143fs Likely pathogenic ★★ same condition
TTN p.Ala19403fs Likely pathogenic ★★ 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/ttn-p-lys8933fs (accessed [today's date]).

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