RUSC2

Summary

RUSC2 (RUN and SH3 domain containing 2, HGNC:23625) is a protein-coding gene on chromosome 9p13.3, encoding AP-4 complex accessory subunit RUSC2 (Q8N2Y8). Associates with the adapter-like complex 4 (AP-4) and may therefore play a role in vesicular trafficking of proteins at the trans-Golgi network.

This gene encodes a RUN and SH3 domain containing protein that interacts with Rab1b and Rab1-binding protein GM130. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 9853 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal recessive 61 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 1,010 total — 33 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 50
• MANE Select transcript: NM_014806

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23625
Approved symbol	RUSC2
Name	RUN and SH3 domain containing 2
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0375
Ensembl gene	ENSG00000198853
Ensembl biotype	protein_coding
OMIM	611053
Entrez	9853

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000361226, ENST00000455600, ENST00000468041, ENST00000866949, ENST00000866950, ENST00000866951, ENST00000970667

RefSeq mRNA: 3 — MANE Select: NM_014806 NM_001135999, NM_001330740, NM_014806

CCDS: CCDS35008

Canonical transcript exons

ENST00000361226 — 12 exons

Exon	Start	End
ENSE00000698716	35555952	35556137
ENSE00000698717	35556308	35556448
ENSE00000698718	35557914	35557990
ENSE00000698719	35558197	35558371
ENSE00000698722	35558462	35558567
ENSE00000698724	35559226	35559272
ENSE00000698758	35560960	35561097
ENSE00000833014	35555060	35555701
ENSE00000833015	35560029	35560851
ENSE00001150521	35490111	35490172
ENSE00001150629	35546430	35548535
ENSE00001851978	35561181	35561895

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 94.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.7075 / max 198.2571, expressed in 1729 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96585	4.1325	1506
96599	3.8524	715
96591	3.8034	1385
96597	2.6504	900
96590	2.5402	1280
96584	1.0418	667
96589	0.8809	604
96583	0.6388	406
96588	0.4065	210
96598	0.2677	142

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	94.95	gold quality
right frontal lobe	UBERON:0002810	94.45	gold quality
popliteal artery	UBERON:0002250	94.29	gold quality
tibial artery	UBERON:0007610	94.28	gold quality
prefrontal cortex	UBERON:0000451	94.18	gold quality
aorta	UBERON:0000947	93.95	gold quality
ascending aorta	UBERON:0001496	93.69	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.69	gold quality
thoracic aorta	UBERON:0001515	93.61	gold quality
cerebellar hemisphere	UBERON:0002245	93.24	gold quality
cerebellar cortex	UBERON:0002129	93.20	gold quality
frontal cortex	UBERON:0001870	92.96	gold quality
right coronary artery	UBERON:0001625	92.85	gold quality
descending thoracic aorta	UBERON:0002345	92.73	gold quality
neocortex	UBERON:0001950	92.71	gold quality
cerebellum	UBERON:0002037	92.65	gold quality
cingulate cortex	UBERON:0003027	92.47	gold quality
anterior cingulate cortex	UBERON:0009835	92.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.34	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.30	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.25	gold quality
type B pancreatic cell	CL:0000169	92.13	gold quality
olfactory bulb	UBERON:0002264	92.09	gold quality
primary visual cortex	UBERON:0002436	92.07	gold quality
middle temporal gyrus	UBERON:0002771	92.03	gold quality
left coronary artery	UBERON:0001626	91.89	gold quality
cerebral cortex	UBERON:0000956	91.65	gold quality
coronary artery	UBERON:0001621	91.44	gold quality
gastrocnemius	UBERON:0001388	91.21	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting RUSC2, 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-5692A	100.00	74.40	6850
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-323B-3P	99.14	68.89	725
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-412-3P	98.86	66.89	712
HSA-MIR-6754-3P	98.84	66.60	889
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-1302	97.92	67.27	844
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-634	97.74	67.11	818
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-4298	97.26	66.59	765
HSA-MIR-874-5P	96.93	63.92	1014

Literature-anchored findings (GeneRIF, showing 9)

• conclude that Iporin might function as a link between the targeting of ER derived vesicles, triggered by the rab1 GTPase and a signaling pathway regulated by molecules containing SH3 and/or poly-proline regions (PMID:15796781)
• Short-term EGF stimulation if of lung tumor cells can increase the interaction between RUSC2 and GIT2, prolonged stimulation leads to a decrease of their interaction through activating Rab35. (PMID:27238570)
• three patients with inherited homozygous nonsense mutations identified in RUSC2 on whole-exome sequencing. All three patients had central hypotonia, microcephaly, and moderate to severe intellectual disability (PMID:27612186)
• AP-4 deficiency causes missorting of ATG9A in diverse cell types, including patient-derived cells, as well as dysregulation of autophagy. (PMID:30262884)
• analysis of structural basis for effector recognition in Rab35/ACAP2 and Rab35/RUSC2 complexes (PMID:30905672)
• Circ_RUSC2 upregulates the expression of miR-661 target gene SYK and regulates the function of vascular smooth muscle cells (PMID:31199889)
• RUSC2 and EHD1 function in a common pathway to positively regulate the basal traffic of Epidermal growth factor receptor from the Golgi compartment to the cell surface to ensure optimal surface receptor levels for subsequent ligand-mediated activation and cellular responses. (PMID:31932478)
• Crystal structure of the FYCO1 RUN domain suggests possible interfaces with small GTPases. (PMID:32744243)
• RUSC2 and WDR47 oppositely regulate kinesin-1-dependent distribution of ATG9A to the cell periphery. (PMID:34432492)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rusc2	ENSDARG00000095288
mus_musculus	Rusc2	ENSMUSG00000035969
rattus_norvegicus	Rusc2	ENSRNOG00000045843

Paralogs (1): RUSC1 (ENSG00000160753)

Protein

Protein identifiers

AP-4 complex accessory subunit RUSC2 — Q8N2Y8 (reviewed: Q8N2Y8)

Alternative names: Interacting protein of Rab1, RUN and SH3 domain-containing protein 2

All UniProt accessions (1): Q8N2Y8

UniProt curated annotations — full annotation on UniProt →

Function. Associates with the adapter-like complex 4 (AP-4) and may therefore play a role in vesicular trafficking of proteins at the trans-Golgi network.

Subunit / interactions. Associated component of the adapter-like complex 4 (AP-4). Interacts with active RAB1A and RAB1B, and with GOLGA2. Interacts (via RUN domain) with RAB35 (GTP-bound form); the interaction recruits RUSC2 to the plasma membrane.

Subcellular location. Cytoplasm. Cytosol. Cell membrane.

Tissue specificity. Widely expressed, with highest levels in brain and testis.

Disease relevance. Intellectual developmental disorder, autosomal recessive 61 (MRT61) [MIM:617773] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT61 patients manifest delayed psychomotor development, moderate to severe intellectual disability, and variable dysmorphic facial features. Refractory seizures and brain abnormalities are present in severely affected patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RUN domain is required for the interaction with RAB1A, RAB1B and RAB35.

RefSeq proteins (3): NP_001129471, NP_001317669, NP_055621* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR004012	Run_dom	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR037213	Run_dom_sf	Homologous_superfamily
IPR047342	RUN_RUSC2	Domain
IPR047343	RUSC1_2	Family

Pfam: PF02759, PF07653

UniProt features (65 total): compositionally biased region 14, region of interest 13, helix 13, modified residue 7, mutagenesis site 7, sequence variant 4, domain 2, turn 2, strand 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6IF2	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N2Y8-F1	45.82	0.15

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 (7): 536, 543, 559, 656, 781, 1368, 1380

Mutagenesis-validated functional residues (7):

Position	Phenotype
1005	decreased interaction with rab35.
1015	strong decrease in interaction with rab35.
1119	loss of interaction with rab35.
1155	loss of interaction with rab35.
1158	loss of interaction with rab35.
1161	decreased interaction with rab35.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 177 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOMF_GTPASE_BINDING, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_UP, chr9p13, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, DURCHDEWALD_SKIN_CARCINOGENESIS_DN, KIM_ALL_DISORDERS_OLIGODENDROCYTE_NUMBER_CORR_UP, RAO_BOUND_BY_SALL4_ISOFORM_B, LIM_MAMMARY_STEM_CELL_UP, ZWANG_CLASS_1_TRANSIENTLY_INDUCED_BY_EGF, BMI1_DN_MEL18_DN.V1_UP, TGFB_UP.V1_UP, FOXD2_TARGET_GENES, HES2_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (2): small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (6): cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasmic vesicle (GO:0031410), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
GTPase binding	1
binding	1
membrane	1
cell periphery	1
intracellular vesicle	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1812 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RUSC2	RAB1B	Q9H0U4	866
RUSC2	RAB1A	P11476	736
RUSC2	GOLGA2	Q08379	734
RUSC2	GTF2F1	P35269	659
RUSC2	RAB35	Q15286	649
RUSC2	MICAL1	Q8TDZ2	642
RUSC2	GRIP2	Q9C0E4	622
RUSC2	AKAP6	Q13023	601
RUSC2	GIT2	Q14161	596
RUSC2	SERINC1	Q9NRX5	591
RUSC2	ZNF668	Q96K58	586
RUSC2	ATG9A	Q7Z3C6	574
RUSC2	AP4B1	Q9Y6B7	573
RUSC2	SERINC3	Q13530	572
RUSC2	AP4S1	Q9Y587	571
RUSC2	ACAP2	Q15057	571

IntAct

48 interactions, top by confidence:

A	B	Type	Score
CDKN1A	CDK1	psi-mi:“MI:0914”(association)	0.900
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
Smc3	RAD21	psi-mi:“MI:0914”(association)	0.600
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
RAB1B	RUSC2	psi-mi:“MI:0915”(physical association)	0.570
RUSC2	RAB1B	psi-mi:“MI:0915”(physical association)	0.570
EGFR	RUSC2	psi-mi:“MI:0915”(physical association)	0.550
KPNB1	POM121C	psi-mi:“MI:0914”(association)	0.530
RUSC2		psi-mi:“MI:0915”(physical association)	0.490
RUSC2	NCL	psi-mi:“MI:0915”(physical association)	0.400
RUSC2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.400
RUSC2	MAGEC1	psi-mi:“MI:0915”(physical association)	0.370
RUSC2	sctL	psi-mi:“MI:0915”(physical association)	0.370
RUSC2	FXR1	psi-mi:“MI:0915”(physical association)	0.370
RUSC2	GIT2	psi-mi:“MI:0915”(physical association)	0.370
RUSC2	RAB1A	psi-mi:“MI:0915”(physical association)	0.370
RUSC2	YPT1	psi-mi:“MI:0915”(physical association)	0.370
MSH6	PARP2	psi-mi:“MI:0914”(association)	0.350
WEE1	CEP350	psi-mi:“MI:0914”(association)	0.350
NFE2L1	WDFY3	psi-mi:“MI:0914”(association)	0.350
KIFAP3	TAF4	psi-mi:“MI:0914”(association)	0.350
Chmp6	NSF	psi-mi:“MI:0914”(association)	0.350
Septin6	SEPTIN10	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350

BioGRID (56): RUSC2 (Two-hybrid), RUSC2 (Reconstituted Complex), GOLGA2 (Two-hybrid), GOLGA2 (Reconstituted Complex), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS), RUSC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8I316, A0A286YDK6, A2A8T7, A5WWA0, A6H7B4, A6NFA0, A6NFR6, A6NGY1, A6NKB5, A6QP24, A8MX80, B2RQL2, O93343, P0C6A0, Q0VD86, Q1EHW4, Q1RN00, Q2HR82, Q32LI3, Q32LN6, Q3B8N5, Q49AJ0, Q5BMD4, Q5DU28, Q5NCP0, Q5SSZ7, Q64ET8, Q66H53, Q68DV7, Q68US1, Q6P4J6, Q6PE65, Q6PG16, Q7SYV9, Q80U22, Q80VY2, Q80W69, Q8BII1, Q8K2F3, Q8N2Y8

Diamond homologs: A1CEK6, A1DFN5, Q4WHP5, Q80U22, Q8BG26, Q8N2Y8, Q9BVN2, Q15811, Q75DS3, Q9WVE9, Q9Z0R4, Q4P5J4, O43281, P38753, Q64355, Q6CVA8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 56 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	153.6×	3e-14
Activation of BAD and translocation to mitochondria	6	130.5×	3e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	115.2×	6e-10
Activation of BH3-only proteins	6	85.1×	4e-09
RHO GTPases activate PKNs	6	54.4×	5e-08
Intrinsic Pathway for Apoptosis	6	50.2×	7e-08
FOXO-mediated transcription	5	48.0×	1e-06
SARS-CoV-1-host interactions	7	35.1×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	8	19.9×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

1010 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	6
Uncertain significance	534
Likely benign	387
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1363847	NM_014806.5(RUSC2):c.547C>T (p.Gln183Ter)	Pathogenic
1369646	NM_014806.5(RUSC2):c.4032G>A (p.Trp1344Ter)	Pathogenic
1390622	NM_014806.5(RUSC2):c.3790C>T (p.Arg1264Ter)	Pathogenic
1408161	NM_014806.5(RUSC2):c.2414dup (p.Glu806fs)	Pathogenic
1431109	NM_014806.5(RUSC2):c.722_727dup (p.Ser243Ter)	Pathogenic
1451964	NM_014806.5(RUSC2):c.1098C>G (p.Tyr366Ter)	Pathogenic
1452261	NM_014806.5(RUSC2):c.2746C>T (p.Arg916Ter)	Pathogenic
1452735	NM_014806.5(RUSC2):c.3734dup (p.Glu1246fs)	Pathogenic
1457058	NM_014806.5(RUSC2):c.2116C>T (p.Gln706Ter)	Pathogenic
1934377	NM_014806.5(RUSC2):c.3995del (p.Glu1332fs)	Pathogenic
1999291	NM_014806.5(RUSC2):c.3810G>A (p.Trp1270Ter)	Pathogenic
2007333	NM_014806.5(RUSC2):c.2198del (p.Pro733fs)	Pathogenic
2014416	NM_014806.5(RUSC2):c.2785dup (p.Ile929fs)	Pathogenic
2023701	NM_014806.5(RUSC2):c.3816C>A (p.Tyr1272Ter)	Pathogenic
2028212	NM_014806.5(RUSC2):c.2695_2698del (p.Tyr899fs)	Pathogenic
2097187	NM_014806.5(RUSC2):c.4052_4053del (p.Ser1351fs)	Pathogenic
2100474	NM_014806.5(RUSC2):c.4207_4210dup (p.Arg1404delinsLysTer)	Pathogenic
2103435	NM_014806.5(RUSC2):c.2887del (p.Asp963fs)	Pathogenic
2106590	NM_014806.5(RUSC2):c.295C>T (p.Arg99Ter)	Pathogenic
2110187	NM_014806.5(RUSC2):c.2581C>T (p.Arg861Ter)	Pathogenic
2697116	NM_014806.5(RUSC2):c.3229C>T (p.Gln1077Ter)	Pathogenic
2726797	NM_014806.5(RUSC2):c.3754dup (p.Glu1252fs)	Pathogenic
2758891	NM_014806.5(RUSC2):c.3758_3759insTG (p.Ala1254fs)	Pathogenic
2824519	NM_014806.5(RUSC2):c.314_317dup (p.Gln106fs)	Pathogenic
2866801	NM_014806.5(RUSC2):c.3361del (p.Trp1121fs)	Pathogenic
2992532	NM_014806.5(RUSC2):c.4047del (p.Asp1350fs)	Pathogenic
3251326	NM_014806.5(RUSC2):c.4227G>A (p.Trp1409Ter)	Pathogenic
3729839	NM_014806.5(RUSC2):c.3073_3076dup (p.Ser1026fs)	Pathogenic
446385	NM_014806.5(RUSC2):c.2596C>T (p.Arg866Ter)	Pathogenic
446386	NM_014806.5(RUSC2):c.3952C>T (p.Arg1318Ter)	Pathogenic

SpliceAI

1792 predictions. Top by Δscore:

Variant	Effect	Δscore
9:35555600:G:GT	donor_gain	1.0000
9:35556306:A:AG	acceptor_gain	1.0000
9:35556307:G:GG	acceptor_gain	1.0000
9:35556383:C:G	donor_gain	1.0000
9:35558325:GC:G	donor_gain	1.0000
9:35558367:GCTAG:G	donor_gain	1.0000
9:35558368:C:G	donor_gain	1.0000
9:35558369:TAGGT:T	donor_loss	1.0000
9:35558370:AGGTA:A	donor_loss	1.0000
9:35558373:T:G	donor_loss	1.0000
9:35558457:CCCA:C	acceptor_loss	1.0000
9:35558460:A:AG	acceptor_gain	1.0000
9:35558461:G:GC	acceptor_loss	1.0000
9:35558461:G:GG	acceptor_gain	1.0000
9:35558461:GGC:G	acceptor_gain	1.0000
9:35558461:GGCCC:G	acceptor_gain	1.0000
9:35558565:CAAGT:C	donor_loss	1.0000
9:35558566:AAG:A	donor_loss	1.0000
9:35558567:AGTG:A	donor_loss	1.0000
9:35558568:G:C	donor_loss	1.0000
9:35558568:G:GG	donor_gain	1.0000
9:35560024:CCTA:C	acceptor_loss	1.0000
9:35560025:CTA:C	acceptor_loss	1.0000
9:35560026:TAG:T	acceptor_loss	1.0000
9:35560027:A:AG	acceptor_gain	1.0000
9:35560027:AGA:A	acceptor_loss	1.0000
9:35560028:G:GG	acceptor_gain	1.0000
9:35560028:GA:G	acceptor_gain	1.0000
9:35560028:GAC:G	acceptor_gain	1.0000
9:35560208:G:GT	donor_gain	1.0000

AlphaMissense

9775 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35547717:T:C	L399P	0.999
9:35547720:T:A	V400D	0.999
9:35555109:G:C	R688S	0.999
9:35555109:G:T	R688S	0.999
9:35547714:A:T	K398I	0.998
9:35547725:T:C	C402R	0.998
9:35555126:T:A	I694N	0.998
9:35556388:T:C	F975L	0.998
9:35556389:T:C	F975S	0.998
9:35556390:T:A	F975L	0.998
9:35556390:T:G	F975L	0.998
9:35561234:T:C	F1468S	0.998
9:35547347:A:C	S276R	0.997
9:35547349:T:A	S276R	0.997
9:35547349:T:G	S276R	0.997
9:35547707:T:C	Y396H	0.997
9:35547710:T:G	Y397D	0.997
9:35548151:T:C	F544L	0.997
9:35548152:T:C	F544S	0.997
9:35548152:T:G	F544C	0.997
9:35548153:T:A	F544L	0.997
9:35548153:T:G	F544L	0.997
9:35555108:G:C	R688T	0.997
9:35555981:T:A	W896R	0.997
9:35555981:T:C	W896R	0.997
9:35555983:G:C	W896C	0.997
9:35555983:G:T	W896C	0.997
9:35557947:T:C	L1006P	0.997
9:35557961:T:C	F1011L	0.997
9:35557963:T:A	F1011L	0.997

dbSNP variants (sampled 300 via entrez): RS1000048378 (9:35489334 C>A), RS1000096393 (9:35550400 C>T), RS1000100229 (9:35489015 G>A), RS1000147863 (9:35544186 T>C,G), RS1000150531 (9:35555558 A>C,G), RS1000184364 (9:35507706 A>C), RS1000248794 (9:35550310 G>C), RS1000297838 (9:35515584 A>G), RS1000322870 (9:35550607 C>T), RS1000329332 (9:35514977 A>G), RS1000487607 (9:35536439 A>C), RS1000535618 (9:35524761 G>A), RS1000616324 (9:35557384 T>C,G), RS1000650560 (9:35500642 C>T), RS1000747142 (9:35510954 GTTACTACTT>G)

Disease associations

OMIM: gene MIM:611053 | disease phenotypes: MIM:617773, MIM:614749

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 61	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 61	Moderate	AR

Mondo (2): intellectual disability, autosomal recessive 61 (MONDO:0030915), hyperphosphatasia with intellectual disability syndrome 2 (MONDO:0013882)

Orphanet (1): Hyperphosphatasia-intellectual disability syndrome (Orphanet:247262)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000268	Dolichocephaly
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000448	Prominent nose
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000664	Synophrys
HP:0000698	Conical tooth
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001182	Tapered finger
HP:0001212	Prominent fingertip pads
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001310	Dysmetria
HP:0001347	Hyperreflexia
HP:0001382	Joint hypermobility
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0002079	Hypoplasia of the corpus callosum

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002874_34	Psoriasis	4.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
lead acetate	increases expression	1
methylparaben	increases expression	1
cupric chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
monomethylarsonous acid	increases expression	1
abrine	increases expression	1
NSC 689534	affects binding, increases expression	1
Temozolomide	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Copper	affects binding, increases expression	1
Estradiol	affects cotreatment, increases expression	1
Phenobarbital	affects expression	1
Selenium	increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Valproic Acid	decreases methylation	1
Cyclosporine	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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