Is TMPO c.565+1272del pathogenic?

TMPO c.565+1272del is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). Ultra-rare (popmax 0.033%, mid); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO c.565+1272del?

TMPO c.565+1272del is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO c.565+1272del in the general population?

TMPO c.565+1272del is ultra-rare (popmax 0.033%, mid) (gnomAD).

TMPO c.565+1272del

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.

rs868100288 · VCV2157371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +1272	deep intronic (+1272 nt into the intron)
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.5	GERP 1.2, phastCons 0.99
Non-coding constraint	Z -2.28	1 kb window · o/e 1.17 · regional · uncalibrated

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000372% 6/1,614,190 alleles · ultra-rare exomes 6/1,461,868 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000254%	393,340

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+1272del
MANE Select: NM_001032283
dbSNP: rs868100288
Type: Deletion
Location: chr12:98533110 (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+1536_565+1543del Uncertain significance ★★ same condition
TMPO c.565+1928del Uncertain significance ★★ same condition
TMPO c.565+1983del Uncertain significance ★★ same condition
TMPO c.565+2304del Uncertain significance ★★ same condition
TMPO c.565+1350_565+1352del Uncertain significance ★ same condition
TMPO c.565+1508_565+1509del Uncertain significance ★ same condition
TMPO c.565+2281_565+2282del Uncertain significance ★ same condition
TMPO p.Lys148fs 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-1272del (accessed [today's date]).

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