SNX4

Chr 3

sorting nexin 4

Also known as: ATG24B

NCBI Gene: 8723 ENSG00000114520 UniProt: O95219

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.

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]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.80

Clinical Summary— SNX4

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Population Constraint (gnomAD)

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

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ClinVar Variants

55 VUS of 78 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

This gene — mechanism propensity

0.7230th %ile

GOF

0.6735th %ile

LOF

0.2582th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

78 submitted variants in ClinVar

ClinVar

Classification Summary

VUS55

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	55	0	55
Likely Benign	1	1	2
Benign	0	0	0
Total	56	1	57

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap SNX4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →