Is TMPO p.Met348Val (c.1042A>G) pathogenic?

TMPO p.Met348Val (c.1042A>G) is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). Ultra-rare (popmax 0.033%, mid); Associated with long QT syndrome.

What condition is associated with TMPO p.Met348Val (c.1042A>G)?

TMPO p.Met348Val (c.1042A>G) is associated with long QT syndrome (ClinVar).

How common is TMPO p.Met348Val (c.1042A>G) in the general population?

TMPO p.Met348Val (c.1042A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

TMPO p.Met348Val

c.1042A>G · rs990534778 · VCV2574012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

long QT syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.252	benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 2.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,511 bp · p 0.089 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,056 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00322% 52/1,612,482 alleles · ultra-rare exomes 43/1,460,194 · genomes 9/152,288 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,028
Remaining individualsnot grpmax-eligible	0.0112%	8,919
European (non-Finnish)	0.00331%	30,221
South Asian	0.0022%	45,521
Admixed American	0.00167%	60,018
Finnishnot grpmax-eligible	0.00156%	64,018

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: TMPO
Protein: p.Met348Val
Coding: c.1042A>G
MANE Select: NM_001032283
dbSNP: rs990534778
Type: single nucleotide variant
Location: chr12:98546410 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 348: the 'disordered' region; the 'binds lamins b' region; the 'nakap95-binding c' region; the 'nucleoplasmic' region

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

Disease context

long QT syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMPO p.Met348Ile Uncertain significance ★ same residue
TMPO c.565+2376C>T Benign/Likely benign ★★ same condition
TMPO c.565+1662T>G Conflicting classifications of pathogenicity ★ ⚠ same condition
TMPO c.565+1005A>G Uncertain significance ★★ ⚠ same type
TMPO c.565+1009T>C Uncertain significance ★★ ⚠ same type
TMPO c.565+1012A>C Uncertain significance ★★ ⚠ same type
TMPO c.565+1017A>G Uncertain significance ★★ ⚠ same type
TMPO c.565+1026A>G Uncertain significance ★★ ⚠ same type

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/tmpo-p-met348val (accessed [today's date]).

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