Is TMPO p.Ser159del (c.472TCT[1]) pathogenic?

TMPO p.Ser159del (c.472TCT[1]) is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). Very rare (popmax 0.00446%, eas); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Ser159del (c.472TCT[1])?

TMPO p.Ser159del (c.472TCT[1]) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Ser159del (c.472TCT[1]) in the general population?

TMPO p.Ser159del (c.472TCT[1]) is very rare (popmax 0.00446%, eas) (gnomAD).

TMPO p.Ser159del

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.472TCT[1] · rs754290044 · VCV2169684

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -2.5, phastCons 1
Overall
CADD	17.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,828 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000186% 3/1,613,772 alleles · very rare exomes 1/1,461,454 · genomes 2/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,414
European (non-Finnish)	8.48e-05%	1,179,920

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.Ser159del
Coding: c.472TCT[1]
MANE Select: NM_001032283
dbSNP: rs754290044
Type: Microsatellite
Location: chr12:98531745 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 159: a modified residue (phosphoserine); 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.Ser159Phe Uncertain significance ★ ⚠ same residue
TMPO c.565+2369_565+2371del Uncertain significance ★★ same condition
TMPO c.565+2461_565+2463del Uncertain significance ★★ same condition
TMPO c.565+1474CT[2] Uncertain significance ★ same condition
TMPO c.565+1615_565+1616del Uncertain significance ★ same condition
TMPO c.565+1694_565+1696del Uncertain significance ★ same condition
TMPO c.565+1718_565+1721del Uncertain significance ★ same condition
TMPO c.565+1813TC[2] 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-ser159del (accessed [today's date]).

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