Is MTO1 p.Pro647= (c.1941C>T) pathogenic?

MTO1 p.Pro647= (c.1941C>T) is classified Likely benign in MTO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). Very rare (popmax 0.00223%, eas); Associated with mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency.

How common is MTO1 p.Pro647= (c.1941C>T) in the general population?

MTO1 p.Pro647= (c.1941C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

MTO1 p.Pro647=

Q: What condition is associated with MTO1 p.Pro647= (c.1941C>T)?

MTO1 p.Pro647= (c.1941C>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.1941C>T · rs747150526 · VCV2159357

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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
Pangolin	Δ0.46	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.038	GERP -3.4, phastCons 0.97
Overall
CADD	12.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00174% 28/1,613,134 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
South Asian	0.0022%	45,413
European (non-Finnish)	0.00195%	51,293
Admixed American	0.00167%	59,770
Remaining individualsnot grpmax-eligible	0.0016%	62,456

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.Pro647=
Coding: c.1941C>T
MANE Select: NM_012123
dbSNP: rs747150526
Type: single nucleotide variant
Location: chr6:73500597 (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.Pro647Leu 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-pro647 (accessed [today's date]).

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