Is TMPO c.565+1983del pathogenic?

TMPO c.565+1983del is classified Uncertain significance in TMPO (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). Very rare (popmax 0.00133%, afr); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO c.565+1983del?

TMPO c.565+1983del is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO c.565+1983del in the general population?

TMPO c.565+1983del is very rare (popmax 0.00133%, afr) (gnomAD).

TMPO c.565+1983del

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.

rs1241598109 · VCV1983592

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 +1983	deep intronic (+1983 nt into the intron)
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.72	GERP -1.1, phastCons 0.004
Non-coding constraint	Z -2.28	1 kb window · o/e 1.17 · regional · uncalibrated
Overall
CADD	0.015	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,926 alleles

Overall 6.2e-05% 1/1,614,086 alleles · very rare exomes 0/1,461,868 · genomes 1/152,218 · joint denominator

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+1983del
MANE Select: NM_001032283
dbSNP: rs1241598109
Type: Deletion
Location: chr12:98533821 (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+2304del Uncertain significance ★★ same condition
TMPO c.565+1272del 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-1983del (accessed [today's date]).

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