SNX25

Chr 4

sorting nexin 25

Also known as: LRP2BP-AS1, MSTP043, SBBI31

NCBI Gene: 83891 ENSG00000109762 UniProt: Q9H3E2 OMIM: 620961

SNX25 encodes a protein that binds phosphatidylinositol and regulates intracellular trafficking, particularly through negative regulation of TGF-beta receptor signaling and receptor degradation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in infancy with seizures and developmental delays. The gene is highly constrained against loss-of-function variants (LOEUF 0.518), reflecting its critical role in cellular function.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable phosphatidylinositol binding activity and type I transforming growth factor beta receptor binding activity. Involved in negative regulation of transforming growth factor beta receptor signaling pathway and receptor catabolic process. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.52

Clinical Summary— SNX25

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

121 VUS of 161 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.000

Z-score 4.18

OE 0.34 (0.23–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.42Z-score

OE missense 0.94 (0.87–1.02)

415 obs / 439.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.23–0.52)

0≤0.351.4

Missense OE?0.94 (0.87–1.02)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 16 / 46.9Missense obs/exp: 415 / 439.6Syn Z: 0.47

This gene — mechanism propensity

0.6646th %ile

GOF

0.7029th %ile

LOF

0.2679th %ile

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

GOFprediction above median

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

161 submitted variants in ClinVar

ClinVar

Classification Summary

VUS121

Likely Benign8

121

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	105	15	0	121
Likely Benign	0	4	2	2	8
Benign	0	0	0	0	0
Total	1	109	17	2	129

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

View in ClinVar →

116 pathogenic / likely-pathogenic (of 150) ClinVar copy-number / structural variants overlap SNX25 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →