Is MTFMT p.Pro12Thr (c.34C>A) pathogenic?

MTFMT p.Pro12Thr (c.34C>A) is classified Conflicting classifications of pathogenicity in MTFMT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0906); Rare (popmax 0.105%, mid); Associated with combined oxidative phosphorylation defect type 15.

What condition is associated with MTFMT p.Pro12Thr (c.34C>A)?

MTFMT p.Pro12Thr (c.34C>A) is associated with combined oxidative phosphorylation defect type 15 (ClinVar).

How common is MTFMT p.Pro12Thr (c.34C>A) in the general population?

MTFMT p.Pro12Thr (c.34C>A) is rare (popmax 0.105%, mid) (gnomAD).

What do computational predictors say about MTFMT p.Pro12Thr (c.34C>A)?

AlphaMissense predicts likely benign (score 0.0906) — an in-silico prediction, not a clinical call.

MTFMT p.Pro12Thr

Q: How is Combined oxidative phosphorylation defect type 15 inherited?

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

c.34C>A · rs933296601 · VCV1031157

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0906 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation defect type 15

Computational evidence

Protein change
AlphaMissense	0.0906	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -6.61	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 0.71	GERP -2.3, phastCons 0.049
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.18 · regional, not allelic
Overall
CADD	0.011	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.105% Middle Eastern · 5/4,776 alleles

Filtering AF 0.0534% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0468%

Overall 0.00434% 65/1,498,690 alleles · rare exomes 55/1,346,524 · genomes 10/152,166 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.105%	955
Admixed American	0.0727%	1,375
Remaining individualsnot grpmax-eligible	0.0138%	7,232
Ashkenazi Jewishnot grpmax-eligible	0.00365%	27,376
European (non-Finnish)	0.00151%	66,139

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: MTFMT
Protein: p.Pro12Thr
Coding: c.34C>A
MANE Select: NM_139242
dbSNP: rs933296601
Type: single nucleotide variant
Location: chr15:65029580 (GRCh38)
Gene constraint: LOEUF 1.304 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.08

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

Disease context

combined oxidative phosphorylation defect type 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 15 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MTFMT p.Pro12Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MTFMT c.722-2A>G Likely pathogenic ★★ same condition
MTFMT p.Arg128Ter Pathogenic/Likely pathogenic ★★ same condition
MTFMT p.Arg332Ter Pathogenic ★★ same condition
MTFMT p.Ser125Leu Pathogenic/Likely pathogenic ★★ same condition
MTFMT p.Ser209Leu Pathogenic ★★ ⚠ same condition
MTFMT p.Arg7Gly Uncertain significance ★★ ⚠ same condition
MTFMT p.Gln355Glu Uncertain significance ★★ ⚠ 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/mtfmt-p-pro12thr (accessed [today's date]).

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