Is TMPO p.Pro62Leu (c.185C>T) pathogenic?

TMPO p.Pro62Leu (c.185C>T) is classified Uncertain significance in TMPO (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-18). AlphaMissense: likely benign (0.2202); Very rare (popmax 0.0011%, sas); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Pro62Leu (c.185C>T)?

TMPO p.Pro62Leu (c.185C>T) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Pro62Leu (c.185C>T) in the general population?

TMPO p.Pro62Leu (c.185C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TMPO p.Pro62Leu (c.185C>T)?

AlphaMissense predicts likely benign (score 0.2202) — an in-silico prediction, not a clinical call.

TMPO p.Pro62Leu

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.185C>T · rs746863579 · VCV1401256

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2202 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.2202	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -5.68	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 5.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	25.7	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

Grpmax group 0.0011% South Asian · 1/90,988 alleles

Overall 0.000124% 2/1,610,806 alleles · very rare exomes 2/1,458,476 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,988
European (non-Finnish)	8.48e-05%	1,179,441

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.Pro62Leu
Coding: c.185C>T
MANE Select: NM_001032283
dbSNP: rs746863579
Type: single nucleotide variant
Location: chr12:98516052 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 62: 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.Pro62= Likely 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-pro62leu (accessed [today's date]).

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