TMED9

Chr 5

transmembrane p24 trafficking protein 9

Also known as: GMP25, HSGP25L2G, p24a2, p24alpha2, p25

NCBI Gene: 54732 ENSG00000184840 OMIM: 620436

The TMED9 protein functions in vesicular protein trafficking within the early secretory pathway, particularly in COPI vesicle-mediated retrograde transport and retention of protein complexes in cis-Golgi membranes. Mutations in TMED9 cause autosomal recessive intellectual disability with hypotonia and dysmorphic features, typically presenting in early childhood. The gene shows low constraint to loss-of-function mutations, which is consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of a family of genes encoding transport proteins located in the endoplasmic reticulum and the Golgi. A similar gene in mouse is the target of microRNA miR-296, which is part of an imprinted cluster. [provided by RefSeq, Jul 2016]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.82

Clinical Summary— TMED9

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

22 VUS of 33 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?

0.82LOEUF

pLI 0.006

Z-score 2.05

OE 0.42 (0.23–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.93Z-score

OE missense 0.77 (0.66–0.91)

104 obs / 134.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.23–0.82)

0≤0.351.4

Missense OE?0.77 (0.66–0.91)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 6 / 14.4Missense obs/exp: 104 / 134.3Syn Z: -0.26

This gene — mechanism propensity

0.7327th %ile

GOF

0.5563th %ile

LOF

0.3163th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

33 submitted variants in ClinVar

ClinVar

Classification Summary

VUS22

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	22	22
Likely Benign	1	1
Benign	0	0
Total	23	23

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

View in ClinVar →

57 pathogenic / likely-pathogenic (of 69) ClinVar copy-number / structural variants overlap TMED9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →