Is TKFC p.Gly290fs (c.869del) pathogenic?

TKFC p.Gly290fs (c.869del) is classified Uncertain significance in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-15). Rare (popmax 0.236%, afr); Associated with Sengers syndrome.

What condition is associated with TKFC p.Gly290fs (c.869del)?

TKFC p.Gly290fs (c.869del) is associated with Sengers syndrome (ClinVar).

How common is TKFC p.Gly290fs (c.869del) in the general population?

TKFC p.Gly290fs (c.869del) is rare (popmax 0.236%, afr) (gnomAD).

TKFC p.Gly290fs

Q: How is Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome inherited?

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

c.869del · VCV3780712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.236%, afr)

Conditions

Sengers syndrome

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 11 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Overall
CADD	31.0	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 0.236% African / African-American · 177/75,042 alleles

Filtering AF 0.207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.197%

Overall 0.0116% 187/1,613,766 alleles · rare exomes 97/1,461,476 · genomes 90/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.236%	424
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Admixed American	0.005%	19,994

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: TKFC
Protein: p.Gly290fs
Coding: c.869del
MANE Select: NM_015533
Type: Deletion
Location: chr11:61343343 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 290: the dhak domain

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

Disease context

Sengers syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TKFC p.Asp43fs Uncertain significance ★ same type

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/tkfc-p-gly290fs (accessed [today's date]).

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