Is MTO1 p.Cys495Arg (c.1483T>C) pathogenic?

MTO1 p.Cys495Arg (c.1483T>C) is classified Uncertain significance in MTO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-25). AlphaMissense: likely pathogenic (0.9553); Very rare (popmax 0.00364%, nfe); Associated with mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency.

How common is MTO1 p.Cys495Arg (c.1483T>C) in the general population?

MTO1 p.Cys495Arg (c.1483T>C) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about MTO1 p.Cys495Arg (c.1483T>C)?

AlphaMissense predicts likely pathogenic (score 0.9553) — an in-silico prediction, not a clinical call.

MTO1 p.Cys495Arg

Q: What condition is associated with MTO1 p.Cys495Arg (c.1483T>C)?

MTO1 p.Cys495Arg (c.1483T>C) 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.1483T>C · rs770891029 · VCV2192183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9553 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Computational evidence

Protein change
AlphaMissense	0.9553	likely pathogenic · top 9% in MTO1
REVEL	0.645	pathogenic-leaning
SaProt	LLR -14.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.0013 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C520R vs ClinVar C495R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00364% European (non-Finnish) · 43/1,179,746 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00273% 44/1,612,632 alleles · very rare exomes 43/1,460,438 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,436
African / African-American	0.00134%	74,832

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.Cys495Arg
Coding: c.1483T>C
MANE Select: NM_012123
dbSNP: rs770891029
Type: single nucleotide variant
Location: chr6:73482466 (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.Cys495= Likely benign ★ 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-cys495arg (accessed [today's date]).

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