SPECC1L

Summary

SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1 like, HGNC:29022) is a protein-coding gene on chromosome 22q11.23, encoding Cytospin-A (Q69YQ0). Involved in cytokinesis and spindle organization.

This gene encodes a coiled-coil domain containing protein. The encoded protein may play a critical role in actin-cytoskeletal reorganization during facial morphogenesis. Mutations in this gene are a cause of oblique facial clefting-1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. A read-through transcript composed of SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and the downstream ADORA2A (adenosine A2a receptor) gene sequence has been identified, but it is thought to be non-coding.

Source: NCBI Gene 23384 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertelorism, Teebi type (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 392 total — 7 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 73
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_015330

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29022
Approved symbol	SPECC1L
Name	sperm antigen with calponin homology and coiled-coil domains 1 like
Location	22q11.23
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0376
Ensembl gene	ENSG00000100014
Ensembl biotype	protein_coding
OMIM	614140
Entrez	23384

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 18 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000314328, ENST00000416735, ENST00000421374, ENST00000437398, ENST00000440893, ENST00000472799, ENST00000541492, ENST00000651059, ENST00000868489, ENST00000868490, ENST00000868491, ENST00000868492, ENST00000868493, ENST00000868494, ENST00000868495, ENST00000933673, ENST00000933674, ENST00000933675, ENST00000948081, ENST00000948082

RefSeq mRNA: 3 — MANE Select: NM_015330 NM_001145468, NM_001254732, NM_015330

CCDS: CCDS33619, CCDS58797

Canonical transcript exons

ENST00000314328 — 17 exons

Exon	Start	End
ENSE00001881826	24414534	24417738
ENSE00003469662	24313313	24313466
ENSE00003473726	24334410	24334573
ENSE00003475905	24363261	24363344
ENSE00003491336	24276700	24276803
ENSE00003491742	24302195	24302384
ENSE00003502222	24347086	24347176
ENSE00003505841	24330256	24330431
ENSE00003514061	24321288	24322918
ENSE00003522695	24365476	24365632
ENSE00003549033	24411588	24411704
ENSE00003630452	24338386	24338477
ENSE00003632304	24369218	24369320
ENSE00003638836	24412648	24412707
ENSE00003669862	24328846	24328919
ENSE00003676353	24324220	24324427
ENSE00003843715	24270831	24270983

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 96.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.0689 / max 41.4998, expressed in 1150 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191373	20.3303	1803
191375	1.6677	908
191372	0.7659	396
191374	0.4012	180

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	96.26	gold quality
tendon	UBERON:0000043	94.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.49	gold quality
endothelial cell	CL:0000115	92.62	gold quality
sural nerve	UBERON:0015488	92.14	gold quality
tendon of biceps brachii	UBERON:0008188	91.97	gold quality
adrenal tissue	UBERON:0018303	91.79	gold quality
parotid gland	UBERON:0001831	91.55	gold quality
esophagus squamous epithelium	UBERON:0006920	91.08	gold quality
islet of Langerhans	UBERON:0000006	90.82	gold quality
ventricular zone	UBERON:0003053	90.52	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	90.27	gold quality
ganglionic eminence	UBERON:0004023	89.86	gold quality
epithelium of esophagus	UBERON:0001976	89.17	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.02	gold quality
lower esophagus	UBERON:0013473	89.01	gold quality
right coronary artery	UBERON:0001625	88.98	gold quality
saphenous vein	UBERON:0007318	88.56	gold quality
stromal cell of endometrium	CL:0002255	88.39	gold quality
embryo	UBERON:0000922	88.37	gold quality
tibia	UBERON:0000979	88.19	gold quality
testis	UBERON:0000473	88.18	gold quality
middle temporal gyrus	UBERON:0002771	87.94	gold quality
popliteal artery	UBERON:0002250	87.93	gold quality
tibial artery	UBERON:0007610	87.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.72	gold quality
cortical plate	UBERON:0005343	87.69	gold quality
amniotic fluid	UBERON:0000173	87.64	gold quality
corpus callosum	UBERON:0002336	87.62	gold quality
tonsil	UBERON:0002372	87.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.54
E-HCAD-5	no	2.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting SPECC1L, 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-188-3P	100.00	68.76	1240
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-4487	99.96	64.58	1252
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954

Literature-anchored findings (GeneRIF, showing 14)

• SPECC1L functions in actin-cytoskeleton reorganization and is required for proper facial morphogenesis. (PMID:21703590)
• The authors use rapid amplification of cDNA ends, tiling arrays, and deep RNA sequencing to identify chimeric transcripts on human chromosomes 21 and 22. They found that for 492 protein coding genes studied, 85% of these genes had boundaries that extended beyond the current annotated termini. (PMID:22238572)
• The authors confirm the role of SPECC1L in orofacial cleft pathogenesis in the first animal model of Tessier cleft, providing morphogenetic insight into the mechanisms of normal craniofacial development and oblique facial cleft pathogenesis (PMID:25357034)
• SPECC1L mutations can cause syndromic forms of facial clefting including some cases of autosomal dominant Opitz G/BBB syndrome. (PMID:25412741)
• two unrelated families with a Teebi hypertelorism-like syndrome and Teebi hypertelorism phenotype who have missense mutations in Sperm Antigen With Calponin Homology And Coiled-Coil Domains (SPECC1L), are reported. (PMID:26111080)
• SPECC1L as a novel modulator of PI3K-AKT signaling and AJ biology, required for neural tube closure and CNCC delamination. (PMID:26787558)
• SPECC1L regulates palate development downstream of IRF6. (PMID:31943082)
• Congenital diaphragmatic hernia as a prominent feature of a SPECC1L-related syndrome. (PMID:32954677)
• Recurrent SPECC1L-NTRK fusions in pediatric sarcoma and brain tumors. (PMID:33144287)
• SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome. (PMID:35205294)
• BCL6-SPECC1L: A Novel Fusion Gene in Nasopharyngeal Carcinoma. (PMID:36412101)
• SPECC1L binds the myosin phosphatase complex MYPT1/PP1beta and can regulate its distribution between microtubules and filamentous actin. (PMID:36634848)
• SPECC1L: a cytoskeletal protein that regulates embryonic tissue dynamics. (PMID:37345651)
• Changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer’s disease. (PMID:38942763)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	specc1la	ENSDARG00000006719
danio_rerio	specc1lb	ENSDARG00000042232
mus_musculus	Specc1l	ENSMUSG00000033444
rattus_norvegicus	Specc1l	ENSRNOG00000001303
drosophila_melanogaster	spdi	FBGN0025633

Paralogs (1): SPECC1 (ENSG00000128487)

Protein

Protein identifiers

Cytospin-A — Q69YQ0 (reviewed: Q69YQ0)

Alternative names: Renal carcinoma antigen NY-REN-22, Sperm antigen with calponin homology and coiled-coil domains 1-like

All UniProt accessions (4): Q69YQ0, A0A494C1J1, C9J8U1, C9JLY8

UniProt curated annotations — full annotation on UniProt →

Function. Involved in cytokinesis and spindle organization. May play a role in actin cytoskeleton organization and microtubule stabilization and hence required for proper cell adhesion and migration.

Subunit / interactions. May interact with both microtubules and actin cytoskeleton.

Subcellular location. Cytoplasm. Cytoskeleton. Spindle. Cell junction. Gap junction.

Disease relevance. Facial clefting, oblique, 1 (OBLFC1) [MIM:600251] A rare form of facial clefting. A facial cleft is any of the fissures between the embryonic prominences that normally unite to form the face. The disease may be caused by variants affecting the gene represented in this entry. Teebi hypertelorism syndrome 1 (TBHS1) [MIM:145420] A form of Teebi hypertelorism syndrome, a syndrome characterized by an abnormally increased distance between ocular orbits, and facial features that can resemble craniofrontonasal dysplasia such as prominent forehead, widow’s peak, heavy and broad eyebrows, long palpebral fissures, ptosis, high and broad nasal bridge, short nose, low-set ears, natal teeth, thin upper lip and a grooved chin. Some affected individuals have limb, urogenital, umbilical and cardiac defects. Developmental delay and/or impaired intellectual development have been observed in some patients. TBHS1 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the cytospin-A family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q69YQ0-1	1	yes
Q69YQ0-2	2

RefSeq proteins (3): NP_001138940, NP_001241661, NP_056145* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001715	CH_dom	Domain
IPR036872	CH_dom_sf	Homologous_superfamily
IPR050540	F-actin_Monoox_Mical	Family

Pfam: PF00307

UniProt features (37 total): sequence variant 11, compositionally biased region 8, modified residue 6, region of interest 4, coiled-coil region 3, sequence conflict 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q69YQ0-F1	67.07	0.37

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 (6): 384, 385, 389, 868, 881, 887

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 357 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_CELL_CELL_ADHESION, GTGCCTT_MIR506, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_CELL_JUNCTION_ORGANIZATION

GO Biological Process (10): negative regulation of microtubule depolymerization (GO:0007026), cell adhesion (GO:0007155), cell migration (GO:0016477), actin cytoskeleton organization (GO:0030036), negative regulation of actin filament depolymerization (GO:0030835), adherens junction organization (GO:0034332), neural crest cell delamination (GO:0036032), cell division (GO:0051301), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), anterior neural tube closure (GO:0061713)

GO Molecular Function (2): beta-catenin binding (GO:0008013), protein binding (GO:0005515)

GO Cellular Component (10): cytoplasm (GO:0005737), microtubule organizing center (GO:0005815), spindle (GO:0005819), gap junction (GO:0005921), actin cytoskeleton (GO:0015629), filamentous actin (GO:0031941), cytoskeleton (GO:0005856), cell-cell junction (GO:0005911), microtubule cytoskeleton (GO:0015630), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of protein depolymerization	2
negative regulation of supramolecular fiber organization	2
cellular process	2
cellular anatomical structure	2
microtubule cytoskeleton	2
intracellular membraneless organelle	2
cytoskeleton	2
microtubule depolymerization	1
negative regulation of microtubule polymerization or depolymerization	1
regulation of microtubule depolymerization	1
cell motility	1
cytoskeleton organization	1
actin filament-based process	1
actin filament depolymerization	1
regulation of actin filament depolymerization	1
negative regulation of cytoskeleton organization	1
cell-cell junction organization	1
delamination	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
neural tube closure	1
tube closure	1
protein binding	1
binding	1
intracellular anatomical structure	1
cell-cell junction	1
actin filament	1
protein-containing complex	1
anchoring junction	1
cell junction	1

Protein interactions and networks

STRING

1272 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPECC1L	NTRK3	Q16288	586
SPECC1L	EML4	Q9HC35	546
SPECC1L	NTRK1	P04629	534
SPECC1L	FKBP15	Q5T1M5	448
SPECC1L	RUFY1	Q96T51	435
SPECC1L	LRRC75B	Q2VPJ9	434
SPECC1L	TCF12	Q99081	433
SPECC1L	RET	P07949	420
SPECC1L	ERC1	Q8IUD2	414
SPECC1L	ANAPC10	Q9UM13	406
SPECC1L	PQBP1	O60828	405
SPECC1L	C22orf15	Q8WYQ4	403
SPECC1L	CMIP	Q8IY22	397
SPECC1L	PTCH1	Q13635	395
SPECC1L	ARHGAP32	A7KAX9	394

IntAct

193 interactions, top by confidence:

A	B	Type	Score
SPC25	NDC80	psi-mi:“MI:0914”(association)	0.940
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
NFKBIA	POLRMT	psi-mi:“MI:0914”(association)	0.670
KRT34	TXLNA	psi-mi:“MI:0914”(association)	0.670
ZNF219	CDK2AP1	psi-mi:“MI:0914”(association)	0.640
LPXN	PCNT	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
G2E3	SPECC1L	psi-mi:“MI:0915”(physical association)	0.560
SPECC1L	PPP1R12C	psi-mi:“MI:0915”(physical association)	0.560
SNW1	SPECC1L	psi-mi:“MI:0915”(physical association)	0.560
SPECC1L	ZNF250	psi-mi:“MI:0915”(physical association)	0.560
ELOA	SPECC1L	psi-mi:“MI:0915”(physical association)	0.560
SPECC1L	EFCAB3	psi-mi:“MI:0915”(physical association)	0.560
ZFHX3	SPECC1L	psi-mi:“MI:0915”(physical association)	0.560
G2E3	SPECC1L	psi-mi:“MI:0914”(association)	0.560
RPS14	MAGEB2	psi-mi:“MI:0914”(association)	0.560

BioGRID (230): SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SPECC1L (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4KEE4, A1Z7Z9, B3LWS4, B3P3M8, B4HEJ6, B4K6I9, B4KKN5, B4LS82, B4M5X4, B4NAD3, B4PSQ2, H2L045, M9MRD1, O96838, P11929, P13496, P14448, P14599, P21520, P47069, P54623, Q09825, Q20924, Q22747, Q23529, Q2KN98, Q2KN99, Q2KNA1, Q2TLY1, Q2TLY2, Q5RJX2, Q69YQ0, Q6AW06, Q7JRE4, Q8MQX9, Q8MSS1, Q8SWR2, Q8T626, Q94071, Q95TU8

Diamond homologs: A5D7D1, D3ZEN0, D3ZHA0, D3ZHV2, D3ZQL6, E1BBG2, F1MF74, F1RA39, F6QZ15, G3MWR8, G3V7L1, L7UZ85, M9MRD1, O13728, O15020, O43707, O75369, O76329, O88990, O94851, O97592, P05094, P05095, P07751, P11277, P11530, P11531, P11532, P11533, P12814, P13395, P13466, P15508, P16086, P16546, P18091, P20111, P21333, P30427, P35609

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 225 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	6	26.2×	1e-05
RHO GTPases activate PAKs	5	17.7×	6e-04
RHO GTPases activate PKNs	8	16.5×	5e-06
Sensory processing of sound	6	12.0×	7e-04
Smooth Muscle Contraction	5	8.6×	7e-03
FCGR3A-mediated phagocytosis	7	8.5×	1e-03
Regulation of PLK1 Activity at G2/M Transition	10	8.2×	5e-05
Loss of Nlp from mitotic centrosomes	8	8.2×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
regulation of synaptic vesicle exocytosis	6	14.2×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	3
Uncertain significance	226
Likely benign	95
Benign	33

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1676270	NM_015330.6(SPECC1L):c.1195C>G (p.Arg399Gly)	Pathogenic
183671	NM_015330.6(SPECC1L):c.1189A>C (p.Thr397Pro)	Pathogenic
3342823	NM_015330.6(SPECC1L):c.1207A>G (p.Met403Val)	Pathogenic
561337	NM_015330.6(SPECC1L):c.1246G>A (p.Ala416Thr)	Pathogenic
561338	NM_015330.6(SPECC1L):c.1258G>A (p.Glu420Lys)	Pathogenic
585312	NM_015330.6(SPECC1L):c.1198_1203del (p.Ile400_His401del)	Pathogenic
585313	NM_015330.6(SPECC1L):c.1260G>C (p.Glu420Asp)	Pathogenic
3256759	NM_015330.6(SPECC1L):c.200C>T (p.Thr67Met)	Likely pathogenic
559898	NM_015330.6(SPECC1L):c.1292T>C (p.Leu431Pro)	Likely pathogenic
561341	NM_015330.6(SPECC1L):c.3026A>C (p.Tyr1009Ser)	Likely pathogenic

SpliceAI

2926 predictions. Top by Δscore:

Variant	Effect	Δscore
22:24270979:GCGCG:G	donor_gain	1.0000
22:24276804:G:GG	donor_gain	1.0000
22:24302193:A:AG	acceptor_gain	1.0000
22:24302193:AG:A	acceptor_loss	1.0000
22:24302194:G:GG	acceptor_gain	1.0000
22:24302194:GATTT:G	acceptor_gain	1.0000
22:24313301:T:TA	acceptor_gain	1.0000
22:24313304:T:TA	acceptor_gain	1.0000
22:24313310:TAG:T	acceptor_loss	1.0000
22:24313311:A:AG	acceptor_gain	1.0000
22:24313312:G:GA	acceptor_gain	1.0000
22:24313312:GA:G	acceptor_gain	1.0000
22:24313312:GAC:G	acceptor_gain	1.0000
22:24313312:GACC:G	acceptor_gain	1.0000
22:24313312:GACCA:G	acceptor_gain	1.0000
22:24322904:G:GT	donor_gain	1.0000
22:24322914:CTAAG:C	donor_loss	1.0000
22:24322915:TAAG:T	donor_loss	1.0000
22:24322916:AAG:A	donor_loss	1.0000
22:24322917:AGGTA:A	donor_loss	1.0000
22:24322918:GGTA:G	donor_loss	1.0000
22:24324219:GGTA:G	acceptor_gain	1.0000
22:24324219:GGTAG:G	acceptor_loss	1.0000
22:24324367:G:GT	donor_gain	1.0000
22:24324423:AGAGA:A	donor_gain	1.0000
22:24324424:GAGA:G	donor_gain	1.0000
22:24324424:GAGAG:G	donor_gain	1.0000
22:24324425:AGA:A	donor_gain	1.0000
22:24324426:GA:G	donor_gain	1.0000
22:24324426:GAG:G	donor_gain	1.0000

AlphaMissense

7353 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:24321759:T:C	L260P	1.000
22:24322221:T:C	L414P	1.000
22:24322226:G:C	A416P	1.000
22:24322233:T:C	L418P	1.000
22:24322242:T:C	L421P	1.000
22:24324359:T:C	L693P	1.000
22:24324377:A:C	Q699P	1.000
22:24324383:G:C	R701P	1.000
22:24330271:T:A	W746R	1.000
22:24330271:T:C	W746R	1.000
22:24330272:G:C	W746S	1.000
22:24330273:G:C	W746C	1.000
22:24330273:G:T	W746C	1.000
22:24330280:T:C	F749L	1.000
22:24330281:T:C	F749S	1.000
22:24330281:T:G	F749C	1.000
22:24330282:T:A	F749L	1.000
22:24330282:T:G	F749L	1.000
22:24330284:A:C	Q750P	1.000
22:24330286:G:C	A751P	1.000
22:24330290:A:C	D752A	1.000
22:24330290:A:G	D752G	1.000
22:24330290:A:T	D752V	1.000
22:24330293:T:A	L753H	1.000
22:24330293:T:C	L753P	1.000
22:24330293:T:G	L753R	1.000
22:24330296:A:C	Q754P	1.000
22:24330301:G:C	A756P	1.000
22:24330302:C:A	A756E	1.000
22:24330305:T:A	V757E	1.000

dbSNP variants (sampled 300 via entrez): RS1000002916 (22:24369698 C>G), RS1000013419 (22:24294519 T>G), RS1000020284 (22:24409920 A>G), RS1000072994 (22:24326204 T>G), RS1000081886 (22:24417341 G>A,C), RS1000085803 (22:24377113 C>T), RS1000100978 (22:24354460 T>C), RS1000125007 (22:24326465 C>T), RS1000187450 (22:24327661 CA>C), RS1000191559 (22:24288508 C>G), RS1000202738 (22:24281745 T>C), RS1000222663 (22:24288728 C>G,T), RS1000239578 (22:24410108 G>A), RS1000286626 (22:24372897 T>C), RS1000312273 (22:24382881 A>G)

Disease associations

OMIM: gene MIM:614140 | disease phenotypes: MIM:145420, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
hypertelorism, Teebi type	Definitive	Autosomal dominant
autosomal dominant Opitz G/BBB syndrome	Strong	Autosomal dominant
Tessier number 4 facial cleft	Strong	Autosomal dominant
Teebi hypertelorism syndrome 1	Strong	Autosomal dominant
commissural facial cleft	Supportive	Autosomal dominant

Mondo (11): oculomaxillofacial dysostosis (MONDO:0015824), Teebi hypertelorism syndrome (MONDO:0030639), Teebi hypertelorism syndrome 1 (MONDO:0800025), intellectual disability (MONDO:0001071), prostate cancer (MONDO:0008315), cleft palate (MONDO:0016064), craniosynostosis (MONDO:0015469), (MONDO:0007779), (MONDO:0007780), Tessier number 4 facial cleft (MONDO:0010850), commissural facial cleft (MONDO:0013300)

Orphanet (8): Tessier number 4 facial cleft (Orphanet:141258), Oculomaxillofacial dysostosis (Orphanet:1794), Opitz GBBB syndrome (Orphanet:2745), SPECC1L-related hypertelorism syndrome (Orphanet:1519), Familial prostate cancer (Orphanet:1331), Cleft palate (Orphanet:2014), Craniosynostosis (Orphanet:1531), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

73 total (30 of 73 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000034	Hydrocele testis
HP:0000049	Shawl scrotum
HP:0000086	Ectopic kidney
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000219	Thin upper lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000233	Thin vermilion border
HP:0000248	Brachycephaly
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000349	Widow’s peak
HP:0000369	Low-set ears
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000568	Microphthalmia
HP:0000574	Thick eyebrow
HP:0000582	Upslanted palpebral fissure
HP:0000589	Coloboma
HP:0000678	Dental crowding

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002481_6	Acne (severe)	6.000000e-07
GCST005196_253	Coronary artery disease	9.000000e-10
GCST005929_5	Severity of nausea and vomiting of pregnancy	6.000000e-09
GCST007234_20	Acne (severe)	1.000000e-08
GCST010479_49	Coronary artery disease	3.000000e-09
GCST011124_11	Caffeine consumption from tea	7.000000e-29
GCST90002396_80	Mean reticulocyte volume	1.000000e-10
GCST90014243_4	Kawasaki disease	3.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009265	nausea and vomiting of pregnancy severity measurement
EFO:0010091	tea consumption measurement
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008265	Macrostomia	C07.465.525.480; C07.650.525.480; C16.131.850.525.480
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C537736	Oculomaxillofacial dysostosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724777 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs5760410	Toxicity	3	methotrexate	Rheumatoid arthritis

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs5751862	SPECC1L		0.00	0
rs5760405	SPECC1L		0.00	0
rs5760410	ADORA2A, SPECC1L	3	2.75	1	methotrexate

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.58	IC50	260	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178956: Inhibition of CYTSA (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.2600	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
titanium dioxide	decreases methylation	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Caffeine	affects phosphorylation	1
Cisplatin	increases expression	1
Endosulfan	decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Phthalic Acids	increases methylation	1
Ribonucleotides	affects binding	1
Dihydrotestosterone	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tretinoin	decreases expression	1
Urethane	increases expression	1
Antirheumatic Agents	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697686	Binding	Inhibition of CYTSA (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy