SNX4

Chr 3

sorting nexin 4

Also known as: ATG24B

NCBI Gene: 8723 ENSG00000114520 UniProt: O95219 OMIM: 605931

SNX4 encodes a sorting nexin protein that regulates endocytosis, intracellular trafficking, transferrin receptor recycling, and autophagosome assembly through its phosphoinositide-binding domain. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and progressive brain atrophy. The gene shows moderate constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein associated with the long isoform of the leptin receptor and with receptor tyrosine kinases for platelet-derived growth factor, insulin, and epidermal growth factor in cell cultures, but its function is unknown. This protein may form oligomeric complexes with family members. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Nov 2012]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.80

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.000

Z-score 2.45

OE 0.53 (0.36–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.89Z-score

OE missense 0.83 (0.74–0.94)

190 obs / 227.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.53 (0.36–0.80)

0≤0.351.4

Missense OE?0.83 (0.74–0.94)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 17 / 31.9Missense obs/exp: 190 / 227.7Syn Z: -0.83

Background carrier burden — how many people carry a rare variant somewhere in SNX4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

567 rare PASS variants

Rare truncating (LoF)

1 in 1,500

113 rare PASS variants

Rare synonymous (reference)

1 in 110

220 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SNX4. 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 190	1 in 1,400
South Asian	~43k	1 in 100	1 in 1,800
Remaining (unassigned)	~30k	1 in 120	1 in 610
European (Finnish)	~27k	1 in 320	1 in 1,800
Admixed American	~22k	1 in 120	1 in 940
African / African American	~21k	1 in 130	1 in 1,700
East Asian	~20k	1 in 130	1 in 1,000
Ashkenazi Jewish	~13k	1 in 670	≈ 1 in 2,600
Middle Eastern	~2,884	1 in 160	≈ 1 in 870

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): 8 of 14 coding exons well covered in gnomAD exomes; exons 1, 5, 7, 8, 10, 14 marginal. Genomes: all 14.? see exons ↓