Is TMPO p.Leu27= (c.81G>T) pathogenic?

TMPO p.Leu27= (c.81G>T) is classified Benign/Likely benign in TMPO (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-23). Ultra-rare (popmax 0.0768%, sas); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Leu27= (c.81G>T)?

TMPO p.Leu27= (c.81G>T) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Leu27= (c.81G>T) in the general population?

TMPO p.Leu27= (c.81G>T) is ultra-rare (popmax 0.0768%, sas) (gnomAD).

TMPO p.Leu27=

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.81G>T · rs549257131 · VCV310760

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0768%, sas)

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 · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -2, phastCons 0.001
Overall
CADD	9.006	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0768% South Asian · 70/91,090 alleles

Filtering AF 0.0624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0571%

Overall 0.00459% 74/1,613,468 alleles · ultra-rare exomes 65/1,461,134 · genomes 9/152,334 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0768%	1,301
African / African-American	0.004%	25,018
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Leu27=
Coding: c.81G>T
MANE Select: NM_001032283
dbSNP: rs549257131
Type: single nucleotide variant
Location: chr12:98515948 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 27: the lem-like domain; 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 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
TMPO c.565+1053A>G 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-leu27 (accessed [today's date]).

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