Is MTFMT p.Arg266Cys (c.796C>T) pathogenic?

MTFMT p.Arg266Cys (c.796C>T) is classified Benign in MTFMT (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.133); Low-frequency (popmax 2.88%, afr); Associated with combined oxidative phosphorylation defect type 15.

What condition is associated with MTFMT p.Arg266Cys (c.796C>T)?

MTFMT p.Arg266Cys (c.796C>T) is associated with combined oxidative phosphorylation defect type 15 (ClinVar).

How common is MTFMT p.Arg266Cys (c.796C>T) in the general population?

MTFMT p.Arg266Cys (c.796C>T) is low-frequency (popmax 2.88%, afr) (gnomAD).

What do computational predictors say about MTFMT p.Arg266Cys (c.796C>T)?

AlphaMissense predicts likely benign (score 0.133) — an in-silico prediction, not a clinical call.

MTFMT p.Arg266Cys

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.796C>T · rs35302908 · VCV138264

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.133 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.88%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined oxidative phosphorylation defect type 15

Computational evidence

Protein change
AlphaMissense	0.133	likely benign
REVEL	0.479	indeterminate
SaProt	LLR -9.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.31	donor loss, 17 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.18 · regional, not allelic
Overall
CADD	29.7	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 2.88% African / African-American · 2,150/74,714 alleles

Filtering AF 2.78% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.74%

Overall 0.156% 2,511/1,606,602 alleles · low-frequency exomes 1,270/1,454,508 · genomes 1,241/152,094 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.88%	35
Remaining individualsnot grpmax-eligible	0.214%	467
Admixed American	0.174%	575
Middle Eastern	0.166%	603
South Asian	0.0211%	4,746
European (non-Finnish)	0.00766%	13,058
East Asian	0.00672%	14,883
Finnishnot grpmax-eligible	0.00314%	31,800

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.Arg266Cys
Coding: c.796C>T
MANE Select: NM_139242
dbSNP: rs35302908
Type: single nucleotide variant
Location: chr15:65016453 (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.Phe58Ile 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-arg266cys (accessed [today's date]).

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