Is MTO1 p.Pro276= (c.828A>G) pathogenic?

MTO1 p.Pro276= (c.828A>G) is classified Likely benign in MTO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-22). Very rare (popmax 0.00111%, sas); Associated with mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency.

How common is MTO1 p.Pro276= (c.828A>G) in the general population?

MTO1 p.Pro276= (c.828A>G) is very rare (popmax 0.00111%, sas) (gnomAD).

MTO1 p.Pro276=

Q: What condition is associated with MTO1 p.Pro276= (c.828A>G)?

MTO1 p.Pro276= (c.828A>G) 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.828A>G · rs2533278451 · VCV2012545

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

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 1.3	GERP -2.7, phastCons 1
Overall
CADD	9.221	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/90,128 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000206% 3/1,456,606 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,128
European (non-Finnish)	0.00017%	588,883

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.Pro276=
Coding: c.828A>G
MANE Select: NM_012123
dbSNP: rs2533278451
Type: single nucleotide variant
Location: chr6:73479734 (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 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
MTO1 p.Leu531Ter 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-pro276 (accessed [today's date]).

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