Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum

Summary

Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum (MONDO:0032903) is a disease caused by SCYL2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SCYL2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum
Mondo ID	MONDO:0032903
OMIM	618766
DOID	DOID:0080980
UMLS	C5231494
MedGen	1684706
GARD	0025768
Is cancer (heuristic)	no

Also known as: AMCNACC · arthrogryposis multiplex congenita, neurogenic, with agenesis of the corpus callosum

Data availability: 13 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › arthrogryposis multiplex congenita › arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum

Related subtypes (23): prenatal-onset spinal muscular atrophy with congenital bone fractures, adducted thumbs-arthrogryposis syndrome, Christian type, arthrogryposis multiplex congenita 2, neurogenic type, fetal akinesia deformation sequence, arthrogryposis multiplex congenita-whistling face syndrome, arthrogryposis-hyperkeratosis syndrome, lethal form, multiple pterygium-malignant hyperthermia syndrome, Marden-Walker syndrome, arthrogryposis due to muscular dystrophy, infantile-onset X-linked spinal muscular atrophy, van den Ende-Gupta syndrome, lethal arthrogryposis-anterior horn cell disease syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, arthrogryposis-like syndrome, autosomal recessive myogenic arthrogryposis multiplex congenita, Wieacker-Wolff syndrome (spectrum), arthrogryposis multiplex congenita 6, arthrogryposis multiplex congenita 3, myogenic type, microphthalmia microtia fetal akinesia, MYBPC1-related autosomal recessive non-lethal arthrogryposis multiplex congenita syndrome, arthrogryposis multiplex congenita 5, hypomyelination neuropathy-arthrogryposis syndrome, arthrogryposis multiplex congenita 7, X-linked

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

13 retrieved; paginated sample, class counts are floors:

5 likely pathogenic, 3 benign, 3 pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2445467	NM_017988.6(SCYL2):c.214_234del (p.Asp72_Glu78del)	SCYL2	Pathogenic	criteria provided, single submitter
810843	NM_017988.6(SCYL2):c.106C>T (p.Arg36Ter)	SCYL2	Pathogenic	criteria provided, single submitter
810844	NM_017988.6(SCYL2):c.1624dup (p.Val542fs)	SCYL2	Pathogenic	no assertion criteria provided
1308643	NM_017988.6(SCYL2):c.97del (p.Asp33fs)	SCYL2	Likely pathogenic	criteria provided, single submitter
1308644	NM_017988.6(SCYL2):c.176dup (p.Glu60fs)	SCYL2	Likely pathogenic	criteria provided, single submitter
2671711	NM_017988.6(SCYL2):c.598dup (p.Cys200fs)	SCYL2	Likely pathogenic	criteria provided, single submitter
4077488	NM_017988.6(SCYL2):c.1215T>A (p.Tyr405Ter)	SCYL2	Likely pathogenic	criteria provided, single submitter
4292525	NM_017988.6(SCYL2):c.2330del (p.Met777fs)	SCYL2	Likely pathogenic	criteria provided, single submitter
3780586	NM_017988.6(SCYL2):c.2287G>A (p.Asp763Asn)	SCYL2	Uncertain significance	criteria provided, single submitter
3900617	NM_017988.6(SCYL2):c.1748TTAATC[1] (p.583LN[1])	SCYL2	Uncertain significance	criteria provided, single submitter
1332927	NM_017988.6(SCYL2):c.177+35C>A	SCYL2	Benign	criteria provided, multiple submitters, no conflicts
1332928	NM_017988.6(SCYL2):c.1096-23T>A	SCYL2	Benign	criteria provided, multiple submitters, no conflicts
1332929	NM_017988.6(SCYL2):c.2167C>T (p.Leu723=)	SCYL2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SCYL2	Strong	Autosomal recessive	arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCYL2	Orphanet:1143	Neurogenic arthrogryposis multiplex congenita

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCYL2	HGNC:19286	ENSG00000136021	Q6P3W7	SCY1-like protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCYL2	SCY1-like protein 2	Component of the AP2-containing clathrin coat that may regulate clathrin-dependent trafficking at plasma membrane, TGN and endosomal system.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCYL2	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, ARM-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	1
mucosa of sigmoid colon	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCYL2	267	ubiquitous	marker	mucosa of sigmoid colon, corpus epididymis, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCYL2	1,084

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCYL2	Q6P3W7	71.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyramidal neuron development	1	2106.5×	0.003	SCYL2
clathrin-dependent endocytosis	1	581.1×	0.005	SCYL2
endosome to lysosome transport	1	337.0×	0.005	SCYL2
receptor internalization	1	324.1×	0.005	SCYL2
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.010	SCYL2
brain development	1	79.5×	0.013	SCYL2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCYL2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	SCYL2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SCYL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.