Is TMPO p.Ala55Val (c.164C>T) pathogenic?

TMPO p.Ala55Val (c.164C>T) is classified Conflicting classifications of pathogenicity in TMPO (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-25). AlphaMissense: likely benign (0.1257); Ultra-rare (popmax 0.0334%, afr); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Ala55Val (c.164C>T)?

TMPO p.Ala55Val (c.164C>T) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Ala55Val (c.164C>T) in the general population?

TMPO p.Ala55Val (c.164C>T) is ultra-rare (popmax 0.0334%, afr) (gnomAD).

What do computational predictors say about TMPO p.Ala55Val (c.164C>T)?

AlphaMissense predicts likely benign (score 0.1257) — an in-silico prediction, not a clinical call.

TMPO p.Ala55Val

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.164C>T · rs756232510 · VCV842091

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1257 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1257	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -6.92	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 2.4	GERP 0.74, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	21.6	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 0.0334% African / African-American · 25/74,938 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00217% 35/1,611,496 alleles · ultra-rare exomes 24/1,459,268 · genomes 11/152,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0334%	2,998
Admixed American	0.0117%	8,562
Remaining individualsnot grpmax-eligible	0.00161%	62,300
European (non-Finnish)	0.00017%	589,783

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.Ala55Val
Coding: c.164C>T
MANE Select: NM_001032283
dbSNP: rs756232510
Type: single nucleotide variant
Location: chr12:98516031 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 55: 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.Ala55Pro Uncertain significance ★ ⚠ same residue
TMPO p.Ala55Thr 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-ala55val (accessed [today's date]).

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