Is TMPO p.Asp119Glu (c.357T>G) pathogenic?

TMPO p.Asp119Glu (c.357T>G) is classified Likely benign in TMPO (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-24). AlphaMissense: likely benign (0.1238); Ultra-rare (popmax 0.0988%, sas); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Asp119Glu (c.357T>G)?

TMPO p.Asp119Glu (c.357T>G) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Asp119Glu (c.357T>G) in the general population?

TMPO p.Asp119Glu (c.357T>G) is ultra-rare (popmax 0.0988%, sas) (gnomAD).

What do computational predictors say about TMPO p.Asp119Glu (c.357T>G)?

AlphaMissense predicts likely benign (score 0.1238) — an in-silico prediction, not a clinical call.

TMPO p.Asp119Glu

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.357T>G · rs765524061 · VCV387399

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1238 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0988%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1238	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -3.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -4.3
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	0.565	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 0.0988% South Asian · 90/91,086 alleles

Filtering AF 0.0823% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0761%

Overall 0.00558% 90/1,613,834 alleles · ultra-rare exomes 84/1,461,616 · genomes 6/152,218 · 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
Protein: p.Asp119Glu
Coding: c.357T>G
MANE Select: NM_001032283
dbSNP: rs765524061
Type: single nucleotide variant
Location: chr12:98527963 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 119: the lem domain; an α-helix; 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-asp119glu (accessed [today's date]).

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