Is TMEM70 p.Pro137Ser (c.409C>T) pathogenic?

TMEM70 p.Pro137Ser (c.409C>T) is classified Uncertain significance in TMEM70 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-05). AlphaMissense: likely benign (0.0809); Very rare (popmax 8.47e-05%, nfe); Associated with mitochondrial complex V (ATP synthase) deficiency, nuclear type 2.

What condition is associated with TMEM70 p.Pro137Ser (c.409C>T)?

TMEM70 p.Pro137Ser (c.409C>T) is associated with mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (ClinVar).

How common is TMEM70 p.Pro137Ser (c.409C>T) in the general population?

TMEM70 p.Pro137Ser (c.409C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TMEM70 p.Pro137Ser (c.409C>T)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

TMEM70 p.Pro137Ser

Q: How is TMEM70-related mitochondrial encephalo-cardio-myopathy inherited?

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

c.409C>T · rs1563699651 · VCV580868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex V (ATP synthase) deficiency, nuclear type 2

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 5,336 bp · p 0.5 · regional, not allelic
Overall
CADD	1.908	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,010 alleles

Overall 6.2e-05% 1/1,614,108 alleles · very rare exomes 1/1,461,828 · genomes 0/152,280 · joint denominator

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: TMEM70
Protein: p.Pro137Ser
Coding: c.409C>T
MANE Select: NM_017866
dbSNP: rs1563699651
Type: single nucleotide variant
Location: chr8:73981247 (GRCh38)
Gene constraint: LOEUF 1.375 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.16

Full TMEM70 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For TMEM70-related mitochondrial encephalo-cardio-myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TMEM70 p.Pro137Leu Uncertain significance ★★ ⚠ same residue
TMEM70 c.317-2A>G Pathogenic/Likely pathogenic ★★ same condition
TMEM70 p.Arg80Ter Pathogenic ★★ same condition
TMEM70 p.Ala174Thr Uncertain significance ★★ ⚠ same condition
TMEM70 p.Ala205Ser Uncertain significance ★★ ⚠ same condition
TMEM70 p.Arg255Trp Uncertain significance ★★ ⚠ same condition
TMEM70 p.Arg80Gln Uncertain significance ★★ ⚠ same condition
TMEM70 p.Asp239His Uncertain significance ★★ ⚠ 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/tmem70-p-pro137ser (accessed [today's date]).

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