TM9SF4

Chr 20

transmembrane 9 superfamily member 4

Also known as: dJ836N17.2

TM9SF4 encodes a transmembrane protein that regulates protein localization to the cell surface and controls V-ATPase complex assembly for intracellular pH regulation in the Golgi apparatus and endosomes. Mutations cause autosomal recessive intellectual disability with microcephaly and seizures, typically presenting in early childhood. This gene is highly constrained against loss-of-function variants in the general population.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
4
Pubs (1 yr)
15
P/LP submissions
0%
P/LP missense
0.25
LOEUF· LoF intol.
Mechanism
Clinical SummaryTM9SF4
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
15 unique Pathogenic / Likely Pathogenic· 52 VUS of 96 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.25LOEUF
pLI 0.999
Z-score 5.30
OE 0.12 (0.060.25)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
2.96Z-score
OE missense 0.58 (0.520.65)
233 obs / 399.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.12 (0.060.25)
00.351.4
Missense OE0.58 (0.520.65)
00.61.4
Synonymous OE0.84
01.21.6
LoF obs/exp: 5 / 42.1Missense obs/exp: 233 / 399.5Syn Z: 1.58

ClinVar Variant Classifications

96 submitted variants in ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic4
VUS52
Likely Benign6
11
Pathogenic
4
Likely Pathogenic
52
VUS
6
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
11
0
11
Likely Pathogenic
0
0
4
0
4
VUS
0
47
5
0
52
Likely Benign
0
3
1
2
6
Benign
0
0
0
0
0
Total05021273

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

View in ClinVar →

Protein Context — Lollipop Plot

TM9SF4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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