TM9SF4

Chr 20

transmembrane 9 superfamily member 4

Also known as: dJ836N17.2

NCBI Gene: 9777 ENSG00000101337 UniProt: Q92544 OMIM: 617727

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.

OMIM ResearchSummary from RefSeq, UniProt

Involved in several processes, including positive regulation of protein localization; response to hypoxia; and vacuolar proton-transporting V-type ATPase complex assembly. Located in Golgi apparatus and early endosome. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.25

LOEUF· LoF intol.

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Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.25LOEUF

pLI 0.999

Z-score 5.30

OE 0.12 (0.06–0.25)

Highly constrained

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

Missense Constraint?

2.96Z-score

OE missense 0.58 (0.52–0.65)

233 obs / 399.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.25)

0≤0.351.4

Missense OE?0.58 (0.52–0.65)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 5 / 42.1Missense obs/exp: 233 / 399.5Syn Z: 1.58

Background carrier burden — how many people carry a rare variant somewhere in TM9SF4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

574 rare PASS variants

Rare truncating (LoF)

1 in 6,300

58 rare PASS variants

Rare synonymous (reference)

1 in 110

318 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TM9SF4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 180	1 in 6,400
South Asian	~43k	1 in 160	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 130	≈ 1 in 15,000
European (Finnish)	~27k	1 in 380	≈ 1 in 13,000
Admixed American	~22k	1 in 190	≈ 1 in 5,600
African / African American	~21k	1 in 130	1 in 3,600
East Asian	~20k	1 in 130	≈ 1 in 9,900
Ashkenazi Jewish	~13k	≈ 1 in 3,300	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 360	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓