Is TSFM p.Arg201fs (c.600dup) pathogenic?

TSFM p.Arg201fs (c.600dup) is classified Pathogenic/Likely pathogenic in TSFM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-27). Very rare (popmax 0.00136%, afr); Associated with fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3.

How common is TSFM p.Arg201fs (c.600dup) in the general population?

TSFM p.Arg201fs (c.600dup) is very rare (popmax 0.00136%, afr) (gnomAD).

TSFM p.Arg201fs

Q: What condition is associated with TSFM p.Arg201fs (c.600dup)?

TSFM p.Arg201fs (c.600dup) is associated with fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 (ClinVar).

Q: How is Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 inherited?

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

c.600dup · rs772810012 · VCV1918350

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Conditions

fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

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 (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.63	GERP -4.1, phastCons 0.037
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 0.00136% African / African-American · 1/73,484 alleles

Filtering AF 0.00025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000161%

Overall 0.000505% 8/1,583,466 alleles · very rare exomes 7/1,431,236 · genomes 1/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,484
European (non-Finnish)	0.000601%	166,392

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: TSFM
Protein: p.Arg201fs
Coding: c.600dup
MANE Select: NM_005726
dbSNP: rs772810012
Type: Duplication
Location: chr12:57796202 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.87 · 1 PDB

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

Disease context

fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TSFM p.Arg201Ter Pathogenic/Likely pathogenic ★★ same residue
TSFM c.484-1003_484-1000dup Likely pathogenic ★ same condition
TSFM p.Arg39fs Likely pathogenic ★ same condition
TSFM p.Arg201Gln Uncertain significance ★ ⚠ same residue
TSFM p.Arg201= Likely benign ★ same residue
TSFM c.231+1G>A Likely pathogenic ★★ same condition
TSFM c.232-2A>G Likely pathogenic ★★ same condition
TSFM c.484-1G>A 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/tsfm-p-arg201fs (accessed [today's date]).

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