Is TMPO c.565+2467T>A pathogenic?

TMPO c.565+2467T>A is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-17). AlphaMissense: likely pathogenic (0.594); Very rare (popmax 0.00432%, nfe); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO c.565+2467T>A?

TMPO c.565+2467T>A is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO c.565+2467T>A in the general population?

TMPO c.565+2467T>A is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about TMPO c.565+2467T>A?

AlphaMissense predicts likely pathogenic (score 0.594) — an in-silico prediction, not a clinical call.

TMPO c.565+2467T>A

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.

rs767216575 · VCV239534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.594	likely pathogenic
REVEL	0.296	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
Splice region	donor +2467	deep intronic (+2467 nt into the intron)
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.2	GERP -1.2, phastCons 1
Non-coding constraint	Z -2.21	1 kb window · o/e 1.17 · regional · uncalibrated
Overall
CADD	16.38	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

Grpmax group 0.00432% European (non-Finnish) · 51/1,179,842 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00329% 53/1,612,928 alleles · very rare exomes 49/1,460,784 · genomes 4/152,144 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,134
Remaining individualsnot grpmax-eligible	0.0016%	62,466
African / African-American	0.00134%	74,894

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
Coding: c.565+2467T>A
MANE Select: NM_001032283
dbSNP: rs767216575
Type: single nucleotide variant
Location: chr12:98534305 (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

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-c-565-plus-2467t-a (accessed [today's date]).

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