Is TMPO p.Pro242Leu (c.725C>T) pathogenic?

TMPO p.Pro242Leu (c.725C>T) is classified Uncertain significance in TMPO (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-15). Very rare (popmax 0.00933%, afr); Associated with TMPO-related disorder.

What condition is associated with TMPO p.Pro242Leu (c.725C>T)?

TMPO p.Pro242Leu (c.725C>T) is associated with TMPO-related disorder (ClinVar).

How common is TMPO p.Pro242Leu (c.725C>T) in the general population?

TMPO p.Pro242Leu (c.725C>T) is very rare (popmax 0.00933%, afr) (gnomAD).

TMPO p.Pro242Leu

c.725C>T · VCV3351017

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00933%, afr)

Conditions

TMPO-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.096	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP -1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	17.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00933% African / African-American · 7/75,032 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00062% 10/1,613,942 alleles · very rare exomes 7/1,461,674 · genomes 3/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00933%	10,719
Remaining individualsnot grpmax-eligible	0.0032%	31,250
East Asian	0.00223%	44,844

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.Pro242Leu
Coding: c.725C>T
MANE Select: NM_001032283
Type: single nucleotide variant
Location: chr12:98544291 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 242: the 'nakap95-binding n' region; the 'disordered' region; the 'nucleoplasmic' region

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

Disease context

TMPO-related disorder

Similar variants

TMPO c.565+2300T>A Uncertain significance ★ same condition
TMPO p.Ala29Val Uncertain significance ⚠ same condition
TMPO p.Ala433Thr Uncertain significance same condition
TMPO p.Asp399Gly Uncertain significance 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

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-pro242leu (accessed [today's date]).

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