Cerebral palsy, spastic quadriplegic, 2

Summary

Cerebral palsy, spastic quadriplegic, 2 (MONDO:0013033) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 111

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral palsy, spastic quadriplegic, 2
Mondo ID	MONDO:0013033
MeSH	C567867
OMIM	612900
DOID	DOID:0081360
UMLS	C2752061
MedGen	442880
GARD	0018309
Is cancer (heuristic)	no

Also known as: cerebral palsy, spastic quadriplegic, 2 · cerebral palsy, spastic quadriplegic, type 2 · CPSQ2 · KANK1 spastic quadriplegia · spastic quadriplegia caused by mutation in KANK1

Data availability: 111 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › cerebral palsy › spastic cerebral palsy › spastic quadriplegic cerebral palsy › cerebral palsy, spastic quadriplegic, 2

Related subtypes (2): cerebral palsy, spastic quadriplegic, 3, neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

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

111 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 25 likely benign, 10 benign/likely benign, 10 conflicting classifications of pathogenicity, 1 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2908	NC_000009.12:g.(606181_654801)_831563del	KANK1	Pathogenic	no assertion criteria provided
1398091	NM_015158.5(KANK1):c.226C>T (p.Pro76Ser)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1408704	NM_015158.5(KANK1):c.3526G>C (p.Glu1176Gln)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1440969	NM_015158.5(KANK1):c.3869C>A (p.Pro1290His)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1441512	NM_015158.5(KANK1):c.3382C>G (p.Gln1128Glu)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446336	NM_015158.5(KANK1):c.1943G>A (p.Arg648Gln)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1468634	NM_015158.5(KANK1):c.3486C>T (p.Gly1162=)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1478990	NM_015158.5(KANK1):c.1909G>A (p.Val637Met)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1525327	NM_015158.5(KANK1):c.2968G>A (p.Ala990Thr)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2129856	NM_015158.5(KANK1):c.2074A>G (p.Ile692Val)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290390	NM_015158.5(KANK1):c.3130C>T (p.Arg1044Trp)	KANK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027945	NM_015158.5(KANK1):c.1086G>C (p.Gln362His)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033737	NM_015158.5(KANK1):c.2020A>G (p.Ser674Gly)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033738	NM_015158.5(KANK1):c.2683C>A (p.Leu895Met)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033739	NM_015158.5(KANK1):c.3709del (p.Ala1237fs)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1048860	NM_015158.5(KANK1):c.1901C>G (p.Ser634Cys)	KANK1	Uncertain significance	no assertion criteria provided
1058403	NM_015158.5(KANK1):c.255A>G (p.Ile85Met)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1299864	NM_015158.5(KANK1):c.3996G>A (p.Pro1332=)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1334871	NM_015158.5(KANK1):c.3213dup (p.Cys1072fs)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1348968	NM_015158.5(KANK1):c.1607C>A (p.Thr536Lys)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1350701	NM_015158.5(KANK1):c.1624G>A (p.Val542Met)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1352355	NM_015158.5(KANK1):c.148G>T (p.Asp50Tyr)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1353694	NM_015158.5(KANK1):c.2342G>C (p.Cys781Ser)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1355220	NM_015158.5(KANK1):c.2153C>G (p.Ala718Gly)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1355698	NM_015158.5(KANK1):c.1882A>G (p.Ile628Val)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1356128	NM_015158.5(KANK1):c.1818_1820del (p.Glu608del)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1360133	NM_015158.5(KANK1):c.2389G>A (p.Val797Met)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1381409	NM_015158.5(KANK1):c.2063C>T (p.Thr688Met)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1383418	NM_015158.5(KANK1):c.3764C>A (p.Ala1255Asp)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1389984	NM_015158.5(KANK1):c.2143C>T (p.Arg715Trp)	KANK1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
KANK1	Supportive	Autosomal recessive	spastic quadriplegic cerebral palsy	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KANK1	Orphanet:210141	Inherited congenital spastic tetraplegia

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KANK1	HGNC:19309	ENSG00000107104	Q14678	KN motif and ankyrin repeat domain-containing protein 1	gencc,clinvar
KANK1-AS1	HGNC:58139	ENSG00000227914		KANK1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KANK1	KN motif and ankyrin repeat domain-containing protein 1	Adapter protein that links structural and signaling protein complexes positioned to guide microtubule and actin cytoskeleton dynamics during cell morphogenesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KANK1	Scaffold/PPI	no		Ankyrin_rpt, KN_motif, Ankyrin_rpt-contain_sf
KANK1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood vessel layer	1
cartilage tissue	1
descending thoracic aorta	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KANK1	291	ubiquitous	marker	blood vessel layer, cartilage tissue, descending thoracic aorta
KANK1-AS1	104		marker	male germ line stem cell (sensu Vertebrata) in testis, sural nerve, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KANK1	1,931
KANK1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KANK1	Q14678	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by membrane-tethered fusions of PDGFRA or PDGFRB	1	2284.0×	0.002	KANK1
Signaling by PDGFR in disease	1	1631.4×	0.002	KANK1
ESR-mediated signaling	1	128.3×	0.020	KANK1
Signaling by Nuclear Receptors	1	102.0×	0.020	KANK1
Estrogen-dependent gene expression	1	75.6×	0.021	KANK1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	KANK1
Disease	1	13.1×	0.087	KANK1
Signal Transduction	1	10.2×	0.098	KANK1

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
negative regulation of lamellipodium morphogenesis	1	8426.0×	0.002	KANK1
podocyte cell migration	1	2407.4×	0.002	KANK1
negative regulation of ruffle assembly	1	2407.4×	0.002	KANK1
cortical microtubule organization	1	1872.4×	0.002	KANK1
negative regulation of substrate adhesion-dependent cell spreading	1	1123.5×	0.003	KANK1
negative regulation of actin filament polymerization	1	936.2×	0.003	KANK1
regulation of establishment of cell polarity	1	936.2×	0.003	KANK1
negative regulation of Rho protein signal transduction	1	766.0×	0.003	KANK1
positive regulation of wound healing	1	526.6×	0.003	KANK1
regulation of Rho protein signal transduction	1	510.7×	0.003	KANK1
positive regulation of Wnt signaling pathway	1	383.0×	0.004	KANK1
negative regulation of insulin receptor signaling pathway	1	374.5×	0.004	KANK1
negative regulation of neuron projection development	1	237.3×	0.006	KANK1
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.008	KANK1
negative regulation of cell migration	1	111.6×	0.010	KANK1
cell population proliferation	1	102.8×	0.010	KANK1
actin cytoskeleton organization	1	79.1×	0.013	KANK1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
KANK1	0	0
KANK1-AS1	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	0
E	Difficult family or no structure, no drug	2	KANK1, KANK1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KANK1	0	—
KANK1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.