Cerebral palsy, spastic quadriplegic, 3

Summary

Cerebral palsy, spastic quadriplegic, 3 (MONDO:0014862) is a disease caused by ADD3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ADD3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral palsy, spastic quadriplegic, 3
Mondo ID	MONDO:0014862
OMIM	617008
DOID	DOID:0081361
UMLS	C4310767
MedGen	934734
GARD	0018310
Is cancer (heuristic)	no

Also known as: ADD3 spastic quadriplegia · cerebral palsy, spastic quadriplegic, 3 · cerebral palsy, spastic quadriplegic, 3; CPSQ3 · cerebral palsy, spastic quadriplegic, type 3 · CPSQ3 · spastic quadriplegia caused by mutation in ADD3

Data availability: 7 ClinVar variants · 3 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, 3

Related subtypes (2): cerebral palsy, spastic quadriplegic, 2, 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

7 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 1 pathogenic/likely pathogenic, 1 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2921286	NM_016824.5(ADD3):c.[1588G>A;86A>G]		Pathogenic	no assertion criteria provided
242273	NM_016824.5(ADD3):c.1100G>A (p.Gly367Asp)	ADD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028030	NM_016824.5(ADD3):c.1372G>A (p.Gly458Arg)	ADD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028031	NM_016824.5(ADD3):c.995A>G (p.Asn332Ser)	ADD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4077842	NM_016824.5(ADD3):c.-29-18442A>G	ADD3	Uncertain significance	criteria provided, single submitter
4077843	NM_016824.5(ADD3):c.-29-34681T>C	ADD3	Uncertain significance	criteria provided, single submitter
3338237	NM_016824.5(ADD3):c.133C>A (p.Leu45Ile)	ADD3	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ADD3	Strong	Autosomal recessive	cerebral palsy, spastic quadriplegic, 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADD3	Orphanet:210141	Inherited congenital spastic tetraplegia

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
ADD3	HGNC:245	ENSG00000148700	Q9UEY8	Gamma-adducin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADD3	Gamma-adducin	Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADD3	Other/Unknown	no		Aldolase_II/adducin_N, Aldolase_II/adducin_N_sf, Aldolase-II_Adducin_sf

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
dorsal motor nucleus of vagus nerve	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADD3	303	ubiquitous	marker	secondary oocyte, oocyte, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADD3	1,882

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADD3	Q9UEY8	66.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 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
Miscellaneous transport and binding events	1	439.2×	0.013	ADD3
RHOF GTPase cycle	1	259.6×	0.013	ADD3
RHOD GTPase cycle	1	203.9×	0.013	ADD3
RHO GTPase cycle	1	60.1×	0.033	ADD3
Signaling by Rho GTPases	1	34.2×	0.040	ADD3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.040	ADD3
Transport of small molecules	1	25.1×	0.045	ADD3
Signal Transduction	1	10.2×	0.098	ADD3

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
positive regulation of cytoskeleton organization	1	2808.7×	0.001	ADD3
barbed-end actin filament capping	1	802.5×	0.002	ADD3
positive regulation of vasoconstriction	1	601.9×	0.002	ADD3
response to xenobiotic stimulus	1	69.1×	0.014	ADD3

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
ADD3	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	1	ADD3

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)
ADD3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.