Is TMPO p.Ala95Val (c.284C>T) pathogenic?

TMPO p.Ala95Val (c.284C>T) is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-22). AlphaMissense: likely pathogenic (0.8267); Absent from gnomAD v4.1; Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Ala95Val (c.284C>T)?

TMPO p.Ala95Val (c.284C>T) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Ala95Val (c.284C>T) in the general population?

TMPO p.Ala95Val (c.284C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMPO p.Ala95Val (c.284C>T)?

AlphaMissense predicts likely pathogenic (score 0.8267) — an in-silico prediction, not a clinical call.

TMPO p.Ala95Val

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.284C>T · rs1565808154 · VCV2748838

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8267 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.8267	likely pathogenic
REVEL	0.172	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	24.7	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

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.Ala95Val
Coding: c.284C>T
MANE Select: NM_001032283
dbSNP: rs1565808154
Type: single nucleotide variant
Location: chr12:98527890 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 95: 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.Ala95Asp Benign ★ ⚠ 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-ala95val (accessed [today's date]).

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