SCYL2

Chr 12AR

SCY1 like pseudokinase 2

Also known as: AMC4, AMCNACC, CVAK104

NCBI Gene: 55681ENSG00000136021UniProt: Q6P3W7OMIM: 616365

The protein functions as a component of clathrin-coated complexes, regulating clathrin-dependent trafficking between the plasma membrane, trans-Golgi network, and endosomal system, and plays an essential role in neuronal function by regulating excitatory receptor expression at synapses. Biallelic mutations cause arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, inherited in an autosomal recessive pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.42), consistent with its role in essential cellular trafficking processes.

OMIMResearchSummary from RefSeq, OMIM, UniProt
ARLOEUF 0.421 OMIM phenotype
Clinical Summary— SCYL2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
15 unique Pathogenic / Likely Pathogenic· 51 VUS of 76 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.42LOEUF
pLI 0.077
Z-score 4.56
OE 0.25 (0.16–0.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.25Z-score
OE missense 0.84 (0.77–0.91)
389 obs / 464.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.25 (0.16–0.42)
0≤0.351.4
Missense OE0.84 (0.77–0.91)
0≤0.61.4
Synonymous OE0.96
0≤1.21.6
LoF obs/exp: 11 / 43.4Missense obs/exp: 389 / 464.9Syn Z: 0.39

ClinVar Variant Classifications

76 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic5
VUS51
Likely Benign6
Benign4
10
Pathogenic
5
Likely Pathogenic
51
VUS
6
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
1
6
0
10
Likely Pathogenic
3
0
2
0
5
VUS
1
42
8
0
51
Likely Benign
0
3
1
2
6
Benign
0
1
2
1
4
Total74719376

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

View in ClinVar →

Protein Context — Lollipop Plot

SCYL2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families.
Al-Kasbi G et al.·Sci Rep
2022
SCYL2-related autosomal recessive neurodevelopmental disorders: Arthrogryposis multiplex congenita-4 and beyond?
Malbos M et al.·Clin Genet
2024Case report
Novel SCYL2 Mutations and Arthrogryposis Multiplex Congenita 4: Case Report and Review of the Literature.
Zamel K et al.·Int J Mol Sci
2025Review
Functional enrichment analysis of LYSET and identification of related hub gene signatures as novel biomarkers to predict prognosis and immune infiltration status of clear cell renal cell carcinoma.
Chen Y et al.·J Cancer Res Clin Oncol
2023Functional
Recessive mutations in SCYL2 cause a novel syndromic form of arthrogryposis in humans.
Seidahmed MZ et al.·Hum Genet
2020Case report
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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