Is TMPO p.Ala433Thr (c.1297G>A) pathogenic?

TMPO p.Ala433Thr (c.1297G>A) is classified Uncertain significance in TMPO (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-11). Very rare (popmax 0.00288%, nfe); Associated with TMPO-related disorder.

What condition is associated with TMPO p.Ala433Thr (c.1297G>A)?

TMPO p.Ala433Thr (c.1297G>A) is associated with TMPO-related disorder (ClinVar).

How common is TMPO p.Ala433Thr (c.1297G>A) in the general population?

TMPO p.Ala433Thr (c.1297G>A) is very rare (popmax 0.00288%, nfe) (gnomAD).

TMPO p.Ala433Thr

c.1297G>A · rs368843309 · VCV3036479

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Conditions

TMPO-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.072	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,511 bp · p 0.089 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00288% European (non-Finnish) · 34/1,180,022 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00211% 34/1,613,928 alleles · very rare exomes 29/1,461,812 · genomes 5/152,116 · 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: TMPO
Protein: p.Ala433Thr
Coding: c.1297G>A
MANE Select: NM_001032283
dbSNP: rs368843309
Type: single nucleotide variant
Location: chr12:98547790 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB

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.Asp399Gly Uncertain significance same condition
TMPO p.Pro242Leu 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-ala433thr (accessed [today's date]).

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