Is TMEM70 p.Pro72Ser (c.214C>T) pathogenic?

TMEM70 p.Pro72Ser (c.214C>T) is classified Uncertain significance in TMEM70 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.1335); Very rare (popmax 0.00401%, afr); Associated with mitochondrial complex V (ATP synthase) deficiency, nuclear type 2.

What condition is associated with TMEM70 p.Pro72Ser (c.214C>T)?

TMEM70 p.Pro72Ser (c.214C>T) is associated with mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (ClinVar).

How common is TMEM70 p.Pro72Ser (c.214C>T) in the general population?

TMEM70 p.Pro72Ser (c.214C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about TMEM70 p.Pro72Ser (c.214C>T)?

AlphaMissense predicts likely benign (score 0.1335) — an in-silico prediction, not a clinical call.

TMEM70 p.Pro72Ser

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.214C>T · rs143292919 · VCV471955

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1335 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.1335	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.27	GERP 0.034, phastCons 0.001
Regional constraint	o/e 1.04	unconstrained · MANE · 5,336 bp · p 0.5 · regional, not allelic
Overall
CADD	18.68	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 0.00401% African / African-American · 3/74,840 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00105% 17/1,613,538 alleles · very rare exomes 12/1,461,684 · genomes 5/151,854 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,947
Remaining individualsnot grpmax-eligible	0.0032%	31,235
South Asian	0.0011%	91,058
European (non-Finnish)	0.000932%	107,257

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.Pro72Ser
Coding: c.214C>T
MANE Select: NM_017866
dbSNP: rs143292919
Type: single nucleotide variant
Location: chr8:73978759 (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.Pro72Leu Uncertain significance ★ ⚠ same residue
TMEM70 p.Pro72Ala 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

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-pro72ser (accessed [today's date]).

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