Is TMEM70 p.Ser46= (c.138G>A) pathogenic?

TMEM70 p.Ser46= (c.138G>A) is classified Likely benign in TMEM70 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). Very rare (popmax 0.000171%, nfe); Associated with mitochondrial complex V (ATP synthase) deficiency, nuclear type 2.

What condition is associated with TMEM70 p.Ser46= (c.138G>A)?

TMEM70 p.Ser46= (c.138G>A) is associated with mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (ClinVar).

How common is TMEM70 p.Ser46= (c.138G>A) in the general population?

TMEM70 p.Ser46= (c.138G>A) is very rare (popmax 0.000171%, nfe) (gnomAD).

TMEM70 p.Ser46=

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.138G>A · rs1319873190 · VCV2801677

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Conditions

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

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 -3.4	GERP -3.7
Overall
CADD	3.416	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000171% European (non-Finnish) · 2/1,169,650 alleles

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

Overall 0.00019% 3/1,577,810 alleles · very rare exomes 3/1,425,462 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00163%	61,346
European (non-Finnish)grpmax	0.000171%	584,826

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser46=
Coding: c.138G>A
MANE Select: NM_017866
dbSNP: rs1319873190
Type: single nucleotide variant
Location: chr8:73976419 (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 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
TMEM70 p.Cys24Arg 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-ser46 (accessed [today's date]).

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