Is TMPO p.Asn49Ser (c.146A>G) pathogenic?

TMPO p.Asn49Ser (c.146A>G) is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-25). AlphaMissense: ambiguous (0.4911); Very rare (popmax 0.00267%, afr); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Asn49Ser (c.146A>G)?

TMPO p.Asn49Ser (c.146A>G) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Asn49Ser (c.146A>G) in the general population?

TMPO p.Asn49Ser (c.146A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TMPO p.Asn49Ser (c.146A>G)?

AlphaMissense predicts ambiguous (score 0.4911) — an in-silico prediction, not a clinical call.

TMPO p.Asn49Ser

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.146A>G · VCV3730151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.4911	ambiguous
REVEL	0.282	benign-leaning
SaProt	LLR -2.04	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	23.4	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 0.00267% African / African-American · 2/74,862 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000559% 9/1,608,588 alleles · very rare exomes 8/1,456,492 · genomes 1/152,096 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,431
East Asian	0.00224%	44,704
European (non-Finnish)	0.000509%	196,463

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.Asn49Ser
Coding: c.146A>G
MANE Select: NM_001032283
Type: single nucleotide variant
Location: chr12:98516013 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 49: the 'disordered' region; the 'linker' region; 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.Asn49Lys 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-asn49ser (accessed [today's date]).

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