WASHC5

Summary

WASHC5 (WASH complex subunit 5, HGNC:28984) is a protein-coding gene on chromosome 8q24.13, encoding WASH complex subunit 5 (Q12768). Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fission of tubules that serve as transport….

This gene encodes a 134 kDa protein named strumpellin that is predicted to have multiple transmembrane domains and a spectrin-repeat-containing domain. This ubiquitously expressed gene has its highest expression in skeletal muscle. The protein is named for Strumpell disease; a form of hereditary spastic paraplegia (HSP). Spastic paraplegias are a diverse group of disorders in which the autosomal dominant forms are characterized by progressive, lower extremity spasticity caused by axonal degeneration in the terminal portions of the longest descending and ascending corticospinal tracts. More than 30 loci (SPG1-33) have been implicated in hereditary spastic paraplegia diseases.

Source: NCBI Gene 9897 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ritscher-Schinzel syndrome 1 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 746 total — 18 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 110
• Druggable target: yes
• MANE Select transcript: NM_014846

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28984
Approved symbol	WASHC5
Name	WASH complex subunit 5
Location	8q24.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164961
Ensembl biotype	protein_coding
OMIM	610657
Entrez	9897

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000318410, ENST00000517845, ENST00000519042, ENST00000519340, ENST00000521109, ENST00000523297, ENST00000523397, ENST00000530856, ENST00000890504, ENST00000890505, ENST00000890506, ENST00000890507, ENST00000920325, ENST00000920326, ENST00000920327, ENST00000920328, ENST00000920329, ENST00000965241, ENST00000965242, ENST00000965243

RefSeq mRNA: 2 — MANE Select: NM_014846 NM_001330609, NM_014846

CCDS: CCDS6355, CCDS83325

Canonical transcript exons

ENST00000318410 — 29 exons

Exon	Start	End
ENSE00000871751	125056677	125056817
ENSE00000871754	125049006	125049185
ENSE00000871757	125043992	125044094
ENSE00000871758	125043825	125043904
ENSE00000871759	125039795	125039898
ENSE00000871760	125038830	125038959
ENSE00000871761	125037237	125037333
ENSE00000871762	125032241	125032394
ENSE00000926381	125050564	125050665
ENSE00000926384	125044536	125044698
ENSE00001089005	125074998	125075111
ENSE00001089008	125057556	125057666
ENSE00001165600	125059222	125059297
ENSE00001173811	125059376	125059542
ENSE00001173818	125061082	125061194
ENSE00001173826	125063522	125063651
ENSE00001173831	125067592	125067719
ENSE00001173836	125073153	125073324
ENSE00001173848	125078738	125078930
ENSE00001173888	125055591	125055671
ENSE00001211235	125076348	125076500
ENSE00001238821	125083713	125084022
ENSE00002115558	125091615	125091792
ENSE00003478939	125083113	125083258
ENSE00003493209	125082383	125082467
ENSE00003528889	125081661	125081761
ENSE00003565650	125028620	125028707
ENSE00003593659	125047207	125047331
ENSE00003601428	125024260	125024673

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 92.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.4677 / max 109.4225, expressed in 1804 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94796	16.4095	1798
94795	2.2347	1241
94793	0.4059	219
94797	0.2562	94
94794	0.1614	47

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	92.90	gold quality
calcaneal tendon	UBERON:0003701	92.61	gold quality
stromal cell of endometrium	CL:0002255	92.34	gold quality
monocyte	CL:0000576	90.68	gold quality
leukocyte	CL:0000738	90.58	gold quality
mononuclear cell	CL:0000842	90.57	gold quality
bone marrow cell	CL:0002092	90.44	gold quality
epithelium of nasopharynx	UBERON:0001951	90.44	gold quality
colonic epithelium	UBERON:0000397	90.19	gold quality
islet of Langerhans	UBERON:0000006	90.13	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.09	gold quality
dorsal root ganglion	UBERON:0000044	90.00	gold quality
ventricular zone	UBERON:0003053	89.88	gold quality
right adrenal gland	UBERON:0001233	89.85	gold quality
left adrenal gland	UBERON:0001234	89.60	gold quality
rectum	UBERON:0001052	89.58	gold quality
left adrenal gland cortex	UBERON:0035825	89.53	gold quality
spinal cord	UBERON:0002240	89.41	gold quality
right adrenal gland cortex	UBERON:0035827	89.40	gold quality
granulocyte	CL:0000094	89.03	gold quality
mammary duct	UBERON:0001765	89.03	gold quality
adrenal gland	UBERON:0002369	89.03	gold quality
bone marrow	UBERON:0002371	89.03	gold quality
adrenal cortex	UBERON:0001235	88.94	gold quality
inferior vagus X ganglion	UBERON:0005363	88.87	gold quality
epithelium of mammary gland	UBERON:0003244	88.65	gold quality
mucosa of transverse colon	UBERON:0004991	88.57	gold quality
spleen	UBERON:0002106	88.54	gold quality
gall bladder	UBERON:0002110	88.40	gold quality
trigeminal ganglion	UBERON:0001675	88.33	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.22
E-GEOD-100618	no	471.19

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

44 targeting WASHC5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-3923	99.52	69.21	446
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-7153-3P	99.00	65.35	608
HSA-MIR-4724-5P	98.87	67.75	1324

Literature-anchored findings (GeneRIF, showing 14)

• The expression of KIAA0196 at chromosomal region 8q24 is significantly higher in prostate carcinomas with gene amplification than in those without it. (PMID:14603436)
• Identified three mutations in the KIAA0196 gene in six families that map to the SPG8 locus. The identification and characterization of the KIAA0196 gene will enable further insight into the pathogenesis of HSP. (PMID:17160902)
• WAFL may play an important role in endocytosis and subsequent membrane trafficking by interacting with AP2 through KIAA0196 and KIAA1033 (PMID:20376207)
• strumpellin is a ubiquitously expressed protein present in cytosolic and endoplasmic reticulum cell fractions. In the human central nervous system strumpellin shows a presynaptic localization. (PMID:20833645)
• Strumpellin disease mutations do not affect its incorporation into the WASH complex or its subcellular localisation. (PMID:23085491)
• We have identified a fourth pathogenic KIAA0196 mutation in a Dutch hereditary spastic paraplegia family, the seventh family worldwide, with a less severe clinical course than described before. (PMID:23455931)
• we identified a novel KIAA0196 missense variant in the proband and her daughter expanding the clinical spectrum of hereditary spastic paraplegia 8. (PMID:23881105)
• To identify the underlying genetic cause of Ritscher-Schinzel syndrome, affected individuals from a First Nations community in Manitoba underwent mutational analysis. All eight patients were homozygous for a novel splice site mutation in KIAA0196. (PMID:24065355)
• Study found a novel KIAA0196 (SPG8) mutation in a Chinese family with spastic paraplegia. (PMID:24824269)
• A mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. (PMID:26965651)
• A novel missense mutation was identified in the KIAA0196 gene in a Japanese patient with SPG8. (PMID:26967522)
• clinical phenotype of the c.1771T>C mutation of KIAA0196 has a considerable heterogeneity and this mutation may be a common pathogenic site of KIAA0196 mutations among Chinese patients with hereditary spastic paraplegia (PMID:31055811)
• SPG8 mutations in Italian families: clinical data and literature review. (PMID:31814071)
• Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes. (PMID:36130690)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	washc5	ENSDARG00000101543
mus_musculus	Washc5	ENSMUSG00000022350
rattus_norvegicus	Washc5	ENSRNOG00000009739
drosophila_melanogaster	Strump	FBGN0036571
caenorhabditis_elegans	T05E7.3	WBGENE00020259

Protein

Protein identifiers

WASH complex subunit 5 — Q12768 (reviewed: Q12768)

Alternative names: Strumpellin, WASH complex subunit strumpellin

All UniProt accessions (3): Q12768, E5RFU6, E7EQI7

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fission of tubules that serve as transport intermediates during endosome sorting. May be involved in axonal outgrowth. Involved in cellular localization of ADRB2. Involved in cellular trafficking of BLOC-1 complex cargos such as ATP7A and VAMP7.

Subunit / interactions. Component of the WASH core complex also described as WASH regulatory complex (SHRC) composed of WASH (WASHC1, WASH2P or WASH3P), WASHC2 (WASHC2A or WASHC2C), WASHC3, WASHC4 and WASHC5. The WASH core complex associates via WASHC2 with the F-actin-capping protein dimer (formed by CAPZA1, CAPZA2 or CAPZA3 and CAPZB) in a transient or substoichiometric manner which was initially described as WASH complex. Interacts with VCP, PI4K2A.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum. Early endosome.

Tissue specificity. Expressed ubiquitously.

Disease relevance. Spastic paraplegia 8, autosomal dominant (SPG8) [MIM:603563] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The disease is caused by variants affecting the gene represented in this entry. Ritscher-Schinzel syndrome 1 (RTSC1) [MIM:220210] A developmental malformation syndrome characterized by craniofacial abnormalities, congenital heart defects, and cerebellar brain malformations. Facial features include prominent occiput, prominent forehead, low-set ears, downslanting palpebral fissures, depressed nasal bridge, and micrognathia. Cardiac defects can include septal defects and aortic stenosis, among others, and brain imaging shows Dandy-Walker malformation, cerebellar vermis hypoplasia, posterior fossa cysts, and ventricular dilatation. Affected individuals have severe developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the strumpellin family.

RefSeq proteins (2): NP_001317538, NP_055661* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019393	WASH_strumpellin	Family

Pfam: PF10266

UniProt features (9 total): sequence variant 6, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12768-F1	90.27	0.65

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 917

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 438 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_NUCLEATION, GOBP_VESICLE_ORGANIZATION, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, HOEGERKORP_CD44_TARGETS_TEMPORAL_DN, GOBP_OOGENESIS, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, PATIL_LIVER_CANCER, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS

GO Biological Process (15): oocyte maturation (GO:0001556), endosome organization (GO:0007032), lysosome organization (GO:0007040), positive regulation of neuron projection development (GO:0010976), protein transport (GO:0015031), endosomal transport (GO:0016197), actin filament polymerization (GO:0030041), protein-containing complex localization (GO:0031503), regulation of Arp2/3 complex-mediated actin nucleation (GO:0034315), polar body extrusion after meiotic divisions (GO:0040038), regulation of actin nucleation (GO:0051125), meiotic spindle assembly (GO:0090306), regulation of vesicle size (GO:0097494), endosome fission (GO:0140285), protein-containing complex organization (GO:0043933)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (8): endosome (GO:0005768), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), early endosome membrane (GO:0031901), neuronal cell body (GO:0043025), WASH complex (GO:0071203), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
endomembrane system	2
cellular anatomical structure	2
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
endomembrane system organization	1
vesicle organization	1
lytic vacuole organization	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
vesicle-mediated transport	1
intracellular transport	1
actin polymerization or depolymerization	1
protein polymerization	1
macromolecule localization	1
Arp2/3 complex-mediated actin nucleation	1
regulation of actin nucleation	1
female meiotic nuclear division	1
meiotic cytokinesis	1
actin nucleation	1
regulation of actin filament organization	1
meiotic spindle organization	1
meiotic chromosome segregation	1
spindle assembly	1
meiotic nuclear division	1
regulation of cellular component size	1
organelle fission	1
cellular component organization	1
binding	1
cytoplasmic vesicle	1
endosome	1
intracellular membrane-bounded organelle	1
early endosome	1
endosome membrane	1
somatodendritic compartment	1

Protein interactions and networks

STRING

880 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WASHC5	WASHC3	Q9Y3C0	998
WASHC5	WASHC4	Q2M389	998
WASHC5	WASHC1	A8K0Z3	996
WASHC5	WASHC2C	Q9Y4E1	961
WASHC5	REEP1	Q9H902	917
WASHC5	SPAST	Q9UBP0	888
WASHC5	ZFYVE27	Q5T4F4	876
WASHC5	NIPA1	Q7RTP0	870
WASHC5	WASHC2A	Q641Q2	840
WASHC5	KIF5A	Q12840	840
WASHC5	VPS35	Q96QK1	806
WASHC5	SNX27	Q96L92	755
WASHC5	VPS26A	O75436	753
WASHC5	ALDH18A1	P54886	733
WASHC5	ATL1	Q8WXF7	728

IntAct

98 interactions, top by confidence:

A	B	Type	Score
VPS29	VPS26C	psi-mi:“MI:0914”(association)	0.760
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
WASHC3	WASH3P	psi-mi:“MI:0914”(association)	0.530
CAPZA1	CNOT1	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
STK16	UNC119B	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
FKBP15	WASHC1	psi-mi:“MI:0403”(colocalization)	0.430
WASHC5	SNX1	psi-mi:“MI:0915”(physical association)	0.400
WASHC5	HSPD1	psi-mi:“MI:0915”(physical association)	0.400
PCNA	WASHC5	psi-mi:“MI:0915”(physical association)	0.400
Capza1		psi-mi:“MI:0915”(physical association)	0.400
CAPZA2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Washc1	COX7A2	psi-mi:“MI:0914”(association)	0.350
VPS26A	LCMT2	psi-mi:“MI:0914”(association)	0.350
VPS26B	KIF1B	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
NS1	ESYT2	psi-mi:“MI:0914”(association)	0.350
Vps29	WASHC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (137): KIAA0196 (Affinity Capture-MS), KIAA0196 (Affinity Capture-MS), KIAA0196 (Synthetic Growth Defect), KIAA0196 (Proximity Label-MS), KIAA0196 (Affinity Capture-MS), KIAA0196 (Affinity Capture-MS), KIAA0196 (Affinity Capture-MS), KIAA0196 (Affinity Capture-MS), KIAA0196 (Affinity Capture-MS), KIAA0196 (Affinity Capture-Western), FKBP15 (Affinity Capture-Western), KIAA0196 (Affinity Capture-MS), KIAA0196 (Proximity Label-MS), KIAA0196 (Affinity Capture-MS), KIAA0196 (Affinity Capture-MS)

ESM2 similar proteins: A5GFY4, A7RU46, B0S6R1, B1AY13, E9Q8I9, O75448, O94915, P28660, P55160, P55161, P55162, P55163, P86409, P97526, Q04690, Q12768, Q299G2, Q4R708, Q4V8B3, Q5F3M0, Q5R414, Q5R5P0, Q5RBT3, Q5RFA0, Q5SQX6, Q5TBA9, Q5VZE5, Q5ZHV2, Q640K3, Q6DIP9, Q6DKG0, Q6GLR7, Q6GQD1, Q6P4S8, Q6PHQ8, Q7L576, Q7T322, Q7TMB8, Q7ZVM1, Q80YV3

Diamond homologs: Q12768, Q54IR8, Q5R5P0, Q6DIP9, Q7ZVM1, Q8C2E7, Q9VUY8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
WASHC5	“form complex”	“WASH complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 112 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Golgi-to-ER retrograde transport	6	12.8×	6e-04
Intra-Golgi and retrograde Golgi-to-ER traffic	7	11.8×	2e-04
Membrane Trafficking	11	6.6×	2e-04
Vesicle-mediated transport	11	6.2×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
retrograde transport, endosome to Golgi	10	21.9×	2e-08
endocytic recycling	6	17.1×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

746 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	18
Uncertain significance	302
Likely benign	173
Benign	148

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1014986	NM_014846.4(WASHC5):c.1424G>A (p.Trp475Ter)	Pathogenic
1162	NM_014846.4(WASHC5):c.1857G>C (p.Leu619Phe)	Pathogenic
1163	NM_014846.4(WASHC5):c.1411A>G (p.Asn471Asp)	Pathogenic
1510703	NM_014846.4(WASHC5):c.913G>T (p.Glu305Ter)	Pathogenic
2218130	NM_014846.4(WASHC5):c.2439del (p.Val814fs)	Pathogenic
2926285	NM_014846.4(WASHC5):c.633T>G (p.Tyr211Ter)	Pathogenic
2938986	NM_014846.4(WASHC5):c.1368del (p.Ser458fs)	Pathogenic
2940559	NM_014846.4(WASHC5):c.2438_2439del (p.Pro813fs)	Pathogenic
3233573	NM_014846.4(WASHC5):c.210del (p.Lys70fs)	Pathogenic
3763973	NM_014846.4(WASHC5):c.3163C>T (p.Gln1055Ter)	Pathogenic
4791041	NM_014846.4(WASHC5):c.1443_1447del (p.Lys481fs)	Pathogenic
4847578	NM_014846.4(WASHC5):c.2812C>T (p.Gln938Ter)	Pathogenic
573798	NM_014846.4(WASHC5):c.3024_3025del (p.Leu1009fs)	Pathogenic
576266	NM_014846.4(WASHC5):c.511C>T (p.Arg171Ter)	Pathogenic
65713	NM_014846.4(WASHC5):c.2087G>C (p.Gly696Ala)	Pathogenic
986025	NM_014846.4(WASHC5):c.232C>T (p.Gln78Ter)	Pathogenic
989010	NM_014846.4(WASHC5):c.1474A>C (p.Thr492Pro)	Pathogenic
989011	NM_014846.4(WASHC5):c.2645T>A (p.Phe882Tyr)	Pathogenic
1030376	NM_014846.4(WASHC5):c.3424-1G>T	Likely pathogenic
1067377	NC_000008.10:g.(?126079753)(126096155_?)del	Likely pathogenic
1183972	NM_014846.4(WASHC5):c.1275dup (p.Glu426fs)	Likely pathogenic
1430473	NM_014846.4(WASHC5):c.2505-1G>C	Likely pathogenic
1985363	NM_014846.4(WASHC5):c.186+1G>C	Likely pathogenic
2576957	NM_014846.4(WASHC5):c.2954+3_2954+4delinsGC	Likely pathogenic
3027461	NM_014846.4(WASHC5):c.711+1G>A	Likely pathogenic
3256753	NM_014846.4(WASHC5):c.1859T>C (p.Val620Ala)	Likely pathogenic
3345558	NM_014846.4(WASHC5):c.1109del (p.Asn370fs)	Likely pathogenic
372817	NM_014846.4(WASHC5):c.1847C>T (p.Ser616Phe)	Likely pathogenic
3780793	NM_014846.4(WASHC5):c.511del (p.Arg171fs)	Likely pathogenic
3897060	NM_014846.4(WASHC5):c.34_35del (p.Gly12fs)	Likely pathogenic

SpliceAI

4463 predictions. Top by Δscore:

Variant	Effect	Δscore
8:125028618:AC:A	donor_gain	1.0000
8:125028618:ACCCT:A	donor_gain	1.0000
8:125028619:CC:C	donor_gain	1.0000
8:125028619:CCCTC:C	donor_gain	1.0000
8:125028708:C:CC	acceptor_gain	1.0000
8:125032219:AGT:A	donor_gain	1.0000
8:125032236:TGTAC:T	donor_loss	1.0000
8:125032237:GTACC:G	donor_loss	1.0000
8:125032238:TA:T	donor_loss	1.0000
8:125032239:A:C	donor_loss	1.0000
8:125032240:CCTTG:C	donor_loss	1.0000
8:125032250:TGCTC:T	donor_gain	1.0000
8:125036157:ATCT:A	donor_gain	1.0000
8:125036158:T:C	donor_gain	1.0000
8:125036166:A:C	donor_gain	1.0000
8:125037235:AC:A	donor_gain	1.0000
8:125037236:CC:C	donor_gain	1.0000
8:125037334:C:CC	acceptor_gain	1.0000
8:125038826:TCA:T	donor_loss	1.0000
8:125038827:CACC:C	donor_loss	1.0000
8:125038828:A:AC	donor_gain	1.0000
8:125038828:AC:A	donor_gain	1.0000
8:125038829:C:CA	donor_loss	1.0000
8:125038829:C:CG	donor_gain	1.0000
8:125038829:CC:C	donor_gain	1.0000
8:125038829:CCTT:C	donor_gain	1.0000
8:125038829:CCTTA:C	donor_gain	1.0000
8:125039793:A:AC	donor_gain	1.0000
8:125039794:C:CC	donor_gain	1.0000
8:125043901:TTTG:T	acceptor_gain	1.0000

AlphaMissense

7667 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:125049058:C:G	R776P	1.000
8:125061101:A:G	L501P	1.000
8:125061188:A:G	L472P	1.000
8:125063572:A:G	L453P	1.000
8:125075066:A:G	W304R	1.000
8:125075066:A:T	W304R	1.000
8:125039894:C:T	G952E	0.999
8:125047288:A:T	I808K	0.999
8:125047314:G:C	S799R	0.999
8:125047314:G:T	S799R	0.999
8:125047316:T:G	S799R	0.999
8:125049059:G:T	R776S	0.999
8:125049106:T:G	D760A	0.999
8:125049107:C:G	D760H	0.999
8:125050622:A:G	L714P	0.999
8:125050630:C:A	R711S	0.999
8:125050630:C:G	R711S	0.999
8:125050631:C:A	R711M	0.999
8:125050631:C:G	R711T	0.999
8:125050634:A:T	I710K	0.999
8:125050637:C:T	G709E	0.999
8:125050638:C:G	G709R	0.999
8:125050638:C:T	G709R	0.999
8:125050646:A:G	L706P	0.999
8:125055602:C:G	G696R	0.999
8:125055632:C:G	G686R	0.999
8:125055667:G:T	A674D	0.999
8:125055668:C:G	A674P	0.999
8:125056780:A:G	L638P	0.999
8:125056801:G:T	P631Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000075659 (8:125036532 G>C), RS1000187601 (8:125071046 T>A), RS1000212557 (8:125024832 G>A), RS1000322792 (8:125029562 A>G), RS1000373696 (8:125055770 T>C,G), RS1000434708 (8:125023803 T>C), RS1000466260 (8:125043393 C>T), RS1000550193 (8:125048583 T>C), RS1000581269 (8:125048744 G>A,C), RS1000582700 (8:125076845 C>T), RS1000626066 (8:125060627 ATAAAC>A), RS1000658106 (8:125028098 A>T), RS1000715158 (8:125076639 C>G), RS1000862140 (8:125035069 T>C), RS1000891427 (8:125082298 G>A,T)

Disease associations

OMIM: gene MIM:610657 | disease phenotypes: MIM:603563, MIM:220210, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
Ritscher-Schinzel syndrome 1	Strong	Autosomal recessive
hereditary spastic paraplegia 8	Strong	Autosomal dominant
Ritscher-Schinzel syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hereditary spastic paraplegia 8	Moderate	AD
Ritscher-Schinzel syndrome 1	Limited	AR

Mondo (5): hereditary spastic paraplegia 8 (MONDO:0011339), Ritscher-Schinzel syndrome (MONDO:0019078), hereditary spastic paraplegia (MONDO:0019064), Ritscher-Schinzel syndrome 1 (MONDO:0009073), intellectual disability (MONDO:0001071)

Orphanet (4): Autosomal dominant spastic paraplegia type 8 (Orphanet:100989), 3C syndrome (Orphanet:7), Hereditary spastic paraplegia (Orphanet:685), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

110 total (30 of 110 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000020	Urinary incontinence
HP:0000023	Inguinal hernia
HP:0000047	Hypospadias
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000235	Abnormal cranial suture/fontanelle morphology
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000269	Prominent occiput
HP:0000316	Hypertelorism
HP:0000329	Facial hemangioma
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000384	Preauricular skin tag
HP:0000431	Wide nasal bridge
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000567	Chorioretinal coloboma
HP:0000589	Coloboma
HP:0000612	Iris coloboma
HP:0000648	Optic atrophy
HP:0000824	Decreased response to growth hormone stimulation test

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000635_6	Response to statin therapy	7.000000e-06
GCST002509_3	Amyotrophic lateral sclerosis	5.000000e-06
GCST002510_1	Amyotrophic lateral sclerosis or frontotemporal dementia	1.000000e-07

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C535313	3C syndrome (supp.)
C580458	Spastic Paraplegia Type 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067349 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.47	Kd	0.337	nM	CHEMBL3752910
9.47	ED50	0.337	nM	CHEMBL3752910
5.51	Kd	3061	nM	CHEMBL5653589
5.51	ED50	3061	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148623: Binding affinity to human KIAA0196 incubated for 45 mins by Kinobead based pull down assay	kd	0.0003	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148623: Binding affinity to human KIAA0196 incubated for 45 mins by Kinobead based pull down assay	kd	3.0611	uM

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	decreases reaction, affects binding	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Benzophenoneidum	increases expression	1
Cadmium	increases abundance, increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651665	Binding	Binding affinity to human KIAA0196 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SU60	HAP1 KIAA0196 (-) 1	Cancer cell line	Male
CVCL_SU61	HAP1 KIAA0196 (-) 2	Cancer cell line	Male
CVCL_SU62	HAP1 KIAA0196 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

248 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)