TMPPE

Chr 3

transmembrane protein with metallophosphoesterase domain

NCBI Gene: 643853 ENSG00000188167 UniProt: Q6ZT21

The TMPPE protein is predicted to function as a hydrolase with metal ion binding activity and is located in cellular membranes. This gene is extremely intolerant to loss-of-function variants (pLI = 0.0009), suggesting mutations would likely cause severe developmental disorders, though specific associated diseases have not yet been established in the literature. The high constraint score indicates that pathogenic variants in this gene would be expected to cause significant clinical phenotypes.

ResearchSummary from RefSeq

Predicted to enable hydrolase activity and metal ion binding activity. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

LOEUF 1.22

Clinical Summary— TMPPE

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 83 VUS of 137 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.22LOEUF

pLI 0.001

Z-score 1.10

OE 0.62 (0.34–1.22)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.08Z-score

OE missense 0.82 (0.73–0.91)

226 obs / 276.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.34–1.22)

0≤0.351.4

Missense OE?0.82 (0.73–0.91)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 6 / 9.7Missense obs/exp: 226 / 276.5Syn Z: 0.25

ClinVar Variant Classifications

137 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic7

VUS83

Likely Benign33

Benign3

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	1	0	6
Likely Pathogenic	5	2	0	0	7
VUS	0	80	3	0	83
Likely Benign	0	4	11	18	33
Benign	0	1	1	1	3
Conflicting	—				4
Total	10	87	16	19	136

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

18 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap TMPPE — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →