SORCS2

Chr 4

sortilin related VPS10 domain containing receptor 2

NCBI Gene: 57537ENSG00000184985UniProt: Q96PQ0

The protein functions as a neurotrophin receptor that forms heterodimers with NGFR to bind precursor forms of NGF and BDNF, regulating dendritic spine density, neurite branching, and synaptic plasticity in the hippocampus. Mutations cause autosomal dominant or recessive neurodevelopmental disorders with intellectual disability, autism spectrum disorder, and epilepsy. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely not tolerated.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
17
Pubs (1 yr)
82
P/LP submissions
0%
P/LP missense
0.43
LOEUF
DN
Mechanism· predicted
Clinical Summary— SORCS2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
82 unique Pathogenic / Likely Pathogenic· 349 VUS of 498 total submissions
Explore recent and relevant literature in Research Assistant →
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.43LOEUF
pLI 0.003
Z-score 5.01
OE 0.28 (0.19–0.43)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.58Z-score
OE missense 0.93 (0.87–1.00)
589 obs / 630.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.28 (0.19–0.43)
0≤0.351.4
Missense OE0.93 (0.87–1.00)
0≤0.61.4
Synonymous OE1.19
0≤1.21.6
LoF obs/exp: 16 / 56.7Missense obs/exp: 589 / 630.3Syn Z: -2.56
DN
0.6357th %ile
GOF
0.5858th %ile
LOF
0.3745th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

498 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic78
Likely Pathogenic4
VUS349
Likely Benign23
Benign11
Conflicting1
78
Pathogenic
4
Likely Pathogenic
349
VUS
23
Likely Benign
11
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
78
0
78
Likely Pathogenic
0
0
4
0
4
VUS
0
335
14
0
349
Likely Benign
0
13
2
8
23
Benign
0
1
1
9
11
Conflicting
—1
Total03499917466

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

View in ClinVar →

Protein Context — Lollipop Plot

SORCS2 · 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

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients