Is TSFM p.Pro28= (c.84C>T) pathogenic?

TSFM p.Pro28= (c.84C>T) is classified Likely benign in TSFM (ClinVar, Single submitter, 2 submitters; last evaluated 2021-01-07). Absent from gnomAD v4.1; Associated with fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3.

How common is TSFM p.Pro28= (c.84C>T) in the general population?

TSFM p.Pro28= (c.84C>T) is absent from gnomAD v4.1 (gnomAD).

TSFM p.Pro28=

Q: What condition is associated with TSFM p.Pro28= (c.84C>T)?

TSFM p.Pro28= (c.84C>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.84C>T · rs776324902 · VCV1669753

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

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.
REVEL	0.01	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -5.4
Overall
CADD	6.673	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSFM
Protein: p.Pro28=
Coding: c.84C>T
MANE Select: NM_005726
dbSNP: rs776324902
Type: single nucleotide variant
Location: chr12:57783136 (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 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
TSFM p.Arg312Trp 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-pro28 (accessed [today's date]).

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