Is TMPO p.Ser166Tyr (c.497C>A) pathogenic?

TMPO p.Ser166Tyr (c.497C>A) is classified Uncertain significance in TMPO (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-25). AlphaMissense: likely benign (0.333); Very rare (popmax 0.00542%, nfe); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Ser166Tyr (c.497C>A)?

TMPO p.Ser166Tyr (c.497C>A) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Ser166Tyr (c.497C>A) in the general population?

TMPO p.Ser166Tyr (c.497C>A) is very rare (popmax 0.00542%, nfe) (gnomAD).

What do computational predictors say about TMPO p.Ser166Tyr (c.497C>A)?

AlphaMissense predicts likely benign (score 0.333) — an in-silico prediction, not a clinical call.

TMPO p.Ser166Tyr

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.497C>A · rs147012167 · VCV202141

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.333	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -9.28	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 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	26.7	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 0.00542% European (non-Finnish) · 64/1,179,876 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.0044% 71/1,613,718 alleles · very rare exomes 68/1,461,572 · genomes 3/152,146 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00542%	18,436
Remaining individualsnot grpmax-eligible	0.0048%	20,823
African / African-American	0.00401%	24,967
Admixed American	0.00167%	59,982

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.Ser166Tyr
Coding: c.497C>A
MANE Select: NM_001032283
dbSNP: rs147012167
Type: single nucleotide variant
Location: chr12:98531770 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 166: a modified residue (phosphoserine); the 'disordered' region; the 'nakap95-binding n' 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.Ser166Cys 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-ser166tyr (accessed [today's date]).

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