Is TMPO p.Val331= (c.993G>A) pathogenic?

TMPO p.Val331= (c.993G>A) is classified Conflicting classifications of pathogenicity in TMPO (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-06-28). Ultra-rare (popmax 0.0505%, mid); Associated with arthrogryposis multiplex congenita.

What condition is associated with TMPO p.Val331= (c.993G>A)?

TMPO p.Val331= (c.993G>A) is associated with arthrogryposis multiplex congenita, fetal akinesia deformation sequence 1 (ClinVar).

How common is TMPO p.Val331= (c.993G>A) in the general population?

TMPO p.Val331= (c.993G>A) is ultra-rare (popmax 0.0505%, mid) (gnomAD).

TMPO p.Val331=

c.993G>A · rs770195100 · VCV692313

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0505%, mid)

Conditions

arthrogryposis multiplex congenita

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.7, phastCons 1
Overall
CADD	14.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0505% Middle Eastern · 3/5,944 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00732%

Overall 0.00193% 31/1,606,482 alleles · ultra-rare exomes 29/1,454,426 · genomes 2/152,056 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0505%	1,981
African / African-American	0.00536%	18,674
Admixed American	0.00333%	29,985
Remaining individualsnot grpmax-eligible	0.00321%	31,114
European (non-Finnish)	0.0017%	58,678

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.Val331=
Coding: c.993G>A
MANE Select: NM_001032283
dbSNP: rs770195100
Type: single nucleotide variant
Location: chr12:98546361 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 331: the 'binds lamins b' region; the 'nakap95-binding c' region; the 'nucleoplasmic' region

Full TMPO gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arthrogryposis multiplex congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: fetal akinesia deformation sequence 1

Similar variants

TMPO c.565+1005A>G Uncertain significance ★★ ⚠ same type
TMPO c.565+1009T>C Uncertain significance ★★ ⚠ same type
TMPO c.565+1012A>C Uncertain significance ★★ ⚠ same type
TMPO c.565+1017A>G Uncertain significance ★★ ⚠ same type
TMPO c.565+1026A>G Uncertain significance ★★ ⚠ same type
TMPO c.565+1029G>T Uncertain significance ★★ ⚠ same type
TMPO c.565+1048G>C Uncertain significance ★★ ⚠ same type
TMPO c.565+1053A>G Uncertain significance ★★ ⚠ same type

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-val331 (accessed [today's date]).

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