Is TMPO p.Pro161His (c.482C>A) pathogenic?

TMPO p.Pro161His (c.482C>A) is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-15). AlphaMissense: ambiguous (0.4061); Absent from gnomAD v4.1; Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Pro161His (c.482C>A)?

TMPO p.Pro161His (c.482C>A) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Pro161His (c.482C>A) in the general population?

TMPO p.Pro161His (c.482C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMPO p.Pro161His (c.482C>A)?

AlphaMissense predicts ambiguous (score 0.4061) — an in-silico prediction, not a clinical call.

TMPO p.Pro161His

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.482C>A · rs1877210566 · VCV2126596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4061 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.4061	ambiguous
REVEL	0.216	benign-leaning
SaProt	LLR -9.38	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMPO
Protein: p.Pro161His
Coding: c.482C>A
MANE Select: NM_001032283
dbSNP: rs1877210566
Type: single nucleotide variant
Location: chr12:98531755 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 161: the 'disordered' region; the 'nakap95-binding n' region; the 'nucleoplasmic' region

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

Disease context

Loeys-Dietz syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TMPO p.Pro161Leu Uncertain significance ★ ⚠ same residue
TMPO c.565+1005A>G Uncertain significance ★★ ⚠ same condition
TMPO c.565+1009T>C Uncertain significance ★★ ⚠ same condition
TMPO c.565+1012A>C Uncertain significance ★★ ⚠ same condition
TMPO c.565+1017A>G Uncertain significance ★★ ⚠ same condition
TMPO c.565+1026A>G Uncertain significance ★★ ⚠ same condition
TMPO c.565+1029G>T Uncertain significance ★★ ⚠ same condition
TMPO c.565+1048G>C 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/tmpo-p-pro161his (accessed [today's date]).

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