Is MTO1 p.Phe4= (c.12C>T) pathogenic?

MTO1 p.Phe4= (c.12C>T) is classified Likely benign in MTO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-24). Very rare (popmax 0.00133%, afr); Associated with mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency.

How common is MTO1 p.Phe4= (c.12C>T) in the general population?

MTO1 p.Phe4= (c.12C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

MTO1 p.Phe4=

Q: What condition is associated with MTO1 p.Phe4= (c.12C>T)?

MTO1 p.Phe4= (c.12C>T) is associated with mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (ClinVar).

Q: How is Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency inherited?

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

c.12C>T · rs374332084 · VCV2174170

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.33	GERP 0.2, phastCons 0.98
Overall
CADD	8.343	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,946 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00093% 15/1,613,362 alleles · very rare exomes 14/1,461,098 · genomes 1/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,946
European (non-Finnish)	0.0011%	90,722
South Asian	0.0011%	91,084

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: MTO1
Protein: p.Phe4=
Coding: c.12C>T
MANE Select: NM_012123
dbSNP: rs374332084
Type: single nucleotide variant
Location: chr6:73461866 (GRCh38)
Gene constraint: LOEUF 0.82 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.95

Full MTO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (Orphanet):

Inheritance: Unknown
Onset: Infancy, Neonatal

Similar variants

MTO1 p.Phe4Leu Uncertain significance ★ ⚠ same residue
MTO1 c.417+2T>C Likely pathogenic ★★ same condition
MTO1 p.Ala428Thr Pathogenic/Likely pathogenic ★★ same condition
MTO1 p.Arg442Ter Pathogenic/Likely pathogenic ★★ same condition
MTO1 p.Arg464Cys Likely pathogenic ★★ same condition
MTO1 p.Arg469Ter Pathogenic/Likely pathogenic ★★ same condition
MTO1 p.Arg484Trp Pathogenic/Likely pathogenic ★★ same condition
MTO1 p.Arg488Ter 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/mto1-p-phe4 (accessed [today's date]).

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