Is TSFM p.Val9Met (c.25G>A) pathogenic?

TSFM p.Val9Met (c.25G>A) is classified Uncertain significance in TSFM (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-11). AlphaMissense: likely benign (0.1715); No allele count reported in gnomAD v4.1 (AN 1,596,148); Associated with fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3.

How common is TSFM p.Val9Met (c.25G>A) in the general population?

TSFM p.Val9Met (c.25G>A) is no allele count reported in gnomAD v4.1 (AN 1,596,148) (gnomAD).

What do computational predictors say about TSFM p.Val9Met (c.25G>A)?

AlphaMissense predicts likely benign (score 0.1715) — an in-silico prediction, not a clinical call.

TSFM p.Val9Met

Q: What condition is associated with TSFM p.Val9Met (c.25G>A)?

TSFM p.Val9Met (c.25G>A) 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.25G>A · VCV4062423

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1715 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,596,148)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Computational evidence

Protein change
AlphaMissense	0.1715	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -8.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.5	GERP -5.1
Regional constraint	o/e 1.15	unconstrained · MANE · 4,331 bp · p 0.04 · regional, not allelic
Overall
CADD	0.822	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,596,148). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TSFM
Protein: p.Val9Met
Coding: c.25G>A
MANE Select: NM_005726
Type: single nucleotide variant
Location: chr12:57782826 (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.Val9= 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
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
TSFM p.Arg201Ter 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-val9met (accessed [today's date]).

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