Is TMPO p.Asn117Ser (c.350A>G) pathogenic?

TMPO p.Asn117Ser (c.350A>G) is classified Likely benign in TMPO (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.1886); Rare (popmax 0.261%, afr); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Asn117Ser (c.350A>G)?

TMPO p.Asn117Ser (c.350A>G) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Asn117Ser (c.350A>G) in the general population?

TMPO p.Asn117Ser (c.350A>G) is rare (popmax 0.261%, afr) (gnomAD).

What do computational predictors say about TMPO p.Asn117Ser (c.350A>G)?

AlphaMissense predicts likely benign (score 0.1886) — an in-silico prediction, not a clinical call.

TMPO p.Asn117Ser

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.350A>G · rs141387097 · VCV202139

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1886 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.261%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1886	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	22.3	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 0.261% African / African-American · 196/75,054 alleles

Filtering AF 0.231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.22%

Overall 0.0131% 211/1,613,952 alleles · rare exomes 114/1,461,598 · genomes 97/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.261%	383
Remaining individualsnot grpmax-eligible	0.016%	6,250
Admixed American	0.005%	20,007
European (non-Finnish)	0.00017%	589,946

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.Asn117Ser
Coding: c.350A>G
MANE Select: NM_001032283
dbSNP: rs141387097
Type: single nucleotide variant
Location: chr12:98527956 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 117: the lem domain; an α-helix; the 'disordered' 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.Asn117= Likely benign ★ same residue
TMPO p.Asn117Asp 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

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-asn117ser (accessed [today's date]).

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