Is TMPO p.Ser18Gly (c.52A>G) pathogenic?

TMPO p.Ser18Gly (c.52A>G) is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-08). AlphaMissense: likely benign (0.1856); Absent from gnomAD v4.1; Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Ser18Gly (c.52A>G)?

TMPO p.Ser18Gly (c.52A>G) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Ser18Gly (c.52A>G) in the general population?

TMPO p.Ser18Gly (c.52A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMPO p.Ser18Gly (c.52A>G)?

AlphaMissense predicts likely benign (score 0.1856) — an in-silico prediction, not a clinical call.

TMPO p.Ser18Gly

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.52A>G · rs2121093002 · VCV1442626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1856 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1856	likely benign
REVEL	0.42	indeterminate
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMPO
Protein: p.Ser18Gly
Coding: c.52A>G
MANE Select: NM_001032283
dbSNP: rs2121093002
Type: single nucleotide variant
Location: chr12:98515919 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 18: the lem-like 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 p.Ser18Arg Uncertain significance ★ ⚠ same residue
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

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-ser18gly (accessed [today's date]).

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