Is TMPO p.Gly128Arg (c.382G>A) pathogenic?

TMPO p.Gly128Arg (c.382G>A) is classified Uncertain significance in TMPO (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-19). AlphaMissense: likely pathogenic (0.8908); Very rare (popmax 0.0022%, sas); Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Gly128Arg (c.382G>A)?

TMPO p.Gly128Arg (c.382G>A) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TMPO p.Gly128Arg (c.382G>A) in the general population?

TMPO p.Gly128Arg (c.382G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about TMPO p.Gly128Arg (c.382G>A)?

AlphaMissense predicts likely pathogenic (score 0.8908) — an in-silico prediction, not a clinical call.

TMPO p.Gly128Arg

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.382G>A · rs200943582 · VCV191788

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.8908	likely pathogenic · top 9% in TMPO
REVEL	0.728	pathogenic-leaning
SaProt	LLR -14.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0022% South Asian · 2/91,074 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000744% 12/1,613,748 alleles · very rare exomes 10/1,461,620 · genomes 2/152,128 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,233
South Asiangrpmax	0.0022%	45,537
Admixed American	0.00167%	59,988
European (non-Finnish)	0.000593%	168,558

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gly128Arg
Coding: c.382G>A
MANE Select: NM_001032283
dbSNP: rs200943582
Type: single nucleotide variant
Location: chr12:98527988 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 128: the lem domain; 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.Gly128Glu 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-gly128arg (accessed [today's date]).

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