Is TSFM p.Arg8= (c.24C>T) pathogenic?

TSFM p.Arg8= (c.24C>T) is classified Conflicting classifications of pathogenicity in TSFM (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-31). Rare (popmax 0.483%, afr); Associated with fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3.

How common is TSFM p.Arg8= (c.24C>T) in the general population?

TSFM p.Arg8= (c.24C>T) is rare (popmax 0.483%, afr) (gnomAD).

TSFM p.Arg8=

Q: What condition is associated with TSFM p.Arg8= (c.24C>T)?

TSFM p.Arg8= (c.24C>T) 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.24C>T · rs138461986 · VCV137764

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.483%, 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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -4
Overall
CADD	6.999	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.483% African / African-American · 361/74,686 alleles

Filtering AF 0.442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.426%

Overall 0.0846% 1,351/1,596,060 alleles · rare exomes 1,051/1,443,744 · genomes 300/152,316 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.23%	81
African / African-Americangrpmax	0.483%	207
Middle Eastern	0.298%	335
Admixed American	0.242%	413
Remaining individualsnot grpmax-eligible	0.204%	490
European (non-Finnish)	0.0293%	3,407
South Asian	0.00341%	29,348

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg8=
Coding: c.24C>T
MANE Select: NM_005726
dbSNP: rs138461986
Type: single nucleotide variant
Location: chr12:57782825 (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.Arg8Cys Uncertain significance ★★ ⚠ same residue
TSFM p.Arg8Pro Uncertain significance ★ ⚠ 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
TSFM c.484-1G>T Likely pathogenic ★★ same condition
TSFM c.57+1G>A Likely pathogenic ★★ same condition
TSFM c.571+1G>C Pathogenic/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-arg8 (accessed [today's date]).

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