Is MTFMT p.Phe58Ile (c.172T>A) pathogenic?

MTFMT p.Phe58Ile (c.172T>A) is classified Benign in MTFMT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.6436); Low-frequency (popmax 1.66%, nfe); Associated with combined oxidative phosphorylation defect type 15.

What condition is associated with MTFMT p.Phe58Ile (c.172T>A)?

MTFMT p.Phe58Ile (c.172T>A) is associated with combined oxidative phosphorylation defect type 15 (ClinVar).

How common is MTFMT p.Phe58Ile (c.172T>A) in the general population?

MTFMT p.Phe58Ile (c.172T>A) is low-frequency (popmax 1.66%, nfe) (gnomAD).

What do computational predictors say about MTFMT p.Phe58Ile (c.172T>A)?

AlphaMissense predicts likely pathogenic (score 0.6436) — an in-silico prediction, not a clinical call.

MTFMT p.Phe58Ile

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.172T>A · rs188718836 · VCV440931

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6436 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.66%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

combined oxidative phosphorylation defect type 15

Computational evidence

Protein change
AlphaMissense	0.6436	likely pathogenic
REVEL	0.596	indeterminate
SaProt	LLR -13.61	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.18 · regional, not allelic
Overall
CADD	25.1	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 1.66% European (non-Finnish) · 18,866/1,135,534 alleles

Filtering AF 1.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.63%

Overall 1.46% 22,125/1,517,602 alleles · low-frequency exomes 20,583/1,365,442 · genomes 1,542/152,160 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.66%	60
Finnishnot grpmax-eligible	1.41%	71
Remaining individualsnot grpmax-eligible	1.37%	73
South Asian	1.17%	86
Middle Eastern	0.844%	119
Admixed American	0.783%	128
Ashkenazi Jewishnot grpmax-eligible	0.502%	199
African / African-American	0.264%	379
Amishnot grpmax-eligible	0.219%	456
East Asian	0.0027%	37,048

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.Phe58Ile
Coding: c.172T>A
MANE Select: NM_139242
dbSNP: rs188718836
Type: single nucleotide variant
Location: chr15:65029442 (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 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
MTFMT p.Arg266Cys Benign ★★ 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-phe58ile (accessed [today's date]).

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