ATP2C2

Summary

ATP2C2 (ATPase secretory pathway Ca2+ transporting 2, HGNC:29103) is a protein-coding gene on chromosome 16q24.1, encoding Calcium-transporting ATPase type 2C member 2 (O75185). ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway.

Enables P-type calcium transporter activity and P-type manganese transporter activity. Predicted to be involved in calcium ion transmembrane transport; intracellular calcium ion homeostasis; and manganese ion transport. Predicted to act upstream of or within mammary gland epithelium development; positive regulation of calcium ion import; and protein localization to plasma membrane. Predicted to be located in trans-Golgi network membrane. Predicted to be active in Golgi membrane; endoplasmic reticulum; and plasma membrane.

Source: NCBI Gene 9914 — RefSeq curated summary.

At a glance

• Gene–disease (curated): speech disorder (Limited, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 422 total — 1 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014861

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29103
Approved symbol	ATP2C2
Name	ATPase secretory pathway Ca2+ transporting 2
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0703, SPCA2
Ensembl gene	ENSG00000064270
Ensembl biotype	protein_coding
OMIM	613082
Entrez	9914

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 15 protein_coding, 8 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 TEC

ENST00000262429, ENST00000416219, ENST00000420010, ENST00000563340, ENST00000564099, ENST00000565546, ENST00000565631, ENST00000565927, ENST00000566874, ENST00000567222, ENST00000567629, ENST00000567892, ENST00000568160, ENST00000569207, ENST00000624933, ENST00000861762, ENST00000861763, ENST00000861764, ENST00000861765, ENST00000861766, ENST00000861767, ENST00000861768, ENST00000861769, ENST00000861770, ENST00000861771, ENST00000957789, ENST00000957790, ENST00000957791

RefSeq mRNA: 3 — MANE Select: NM_014861 NM_001286527, NM_001291454, NM_014861

CCDS: CCDS42207, CCDS67088

Canonical transcript exons

ENST00000262429 — 27 exons

Exon	Start	End
ENSE00001301133	84405128	84405244
ENSE00001531009	84398499	84398609
ENSE00003459181	84442510	84442599
ENSE00003461166	84410568	84410603
ENSE00003489150	84460654	84460801
ENSE00003499787	84459120	84459188
ENSE00003530372	84422390	84422539
ENSE00003530833	84454818	84454984
ENSE00003534916	84439166	84439290
ENSE00003544953	84423188	84423263
ENSE00003552595	84453138	84453235
ENSE00003571049	84408405	84408494
ENSE00003578161	84415483	84415591
ENSE00003578582	84461988	84462129
ENSE00003584638	84448533	84448689
ENSE00003595031	84422629	84422697
ENSE00003596321	84410704	84410765
ENSE00003608652	84453321	84453371
ENSE00003611447	84451921	84452091
ENSE00003633105	84461714	84461812
ENSE00003643210	84439427	84439524
ENSE00003643275	84459270	84459386
ENSE00003671654	84446329	84446430
ENSE00003685150	84440857	84440958
ENSE00003687755	84425735	84425801
ENSE00003899791	84368538	84368714
ENSE00004282496	84463614	84464187

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 96.73.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1358 / max 877.6138, expressed in 314 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155331	1.6336	285
155330	0.5022	140

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	96.73	gold quality
mucosa of transverse colon	UBERON:0004991	95.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.14	gold quality
bronchial epithelial cell	CL:0002328	95.13	gold quality
epithelium of bronchus	UBERON:0002031	94.81	gold quality
bronchus	UBERON:0002185	94.18	gold quality
colonic mucosa	UBERON:0000317	93.53	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.70	gold quality
right uterine tube	UBERON:0001302	92.13	gold quality
skin of abdomen	UBERON:0001416	90.26	gold quality
skin of leg	UBERON:0001511	90.04	gold quality
nasal cavity epithelium	UBERON:0005384	89.46	gold quality
ileal mucosa	UBERON:0000331	88.98	gold quality
transverse colon	UBERON:0001157	88.59	gold quality
colonic epithelium	UBERON:0000397	87.60	gold quality
zone of skin	UBERON:0000014	87.47	gold quality
secondary oocyte	CL:0000655	86.94	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.72	gold quality
minor salivary gland	UBERON:0001830	86.20	gold quality
upper lobe of left lung	UBERON:0008952	86.05	gold quality
duodenum	UBERON:0002114	85.87	gold quality
jejunal mucosa	UBERON:0000399	85.77	gold quality
lower esophagus mucosa	UBERON:0035834	85.63	gold quality
oocyte	CL:0000023	85.33	gold quality
upper lobe of lung	UBERON:0008948	85.15	gold quality
pancreatic ductal cell	CL:0002079	84.94	silver quality
small intestine Peyer’s patch	UBERON:0003454	84.25	gold quality
buccal mucosa cell	CL:0002336	83.82	gold quality
small intestine	UBERON:0002108	83.59	gold quality
right lobe of thyroid gland	UBERON:0001119	83.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.97
E-MTAB-6678	yes	8.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting ATP2C2, 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-548C-3P	99.99	74.01	7587
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-8070	99.07	69.30	1303
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-4289	98.26	66.90	810
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-2114-5P	96.00	64.56	617
HSA-MIR-151A-5P	95.79	68.73	162
HSA-MIR-151B	95.79	68.73	162
HSA-MIR-6840-5P	88.69	60.91	68

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 18)

• SPCA2 may have a more specialized role in mammalian cells, possibly in cellular detoxification of Mn2+ ions. (PMID:15677451)
• hSPCA2 has the ability to transport Ca(2+) and Mn(2+); both its transport and Ca(2+)- and Mn(2+)-dependent phosphoprotein intermediate formation functions are insensitive to thapsigargin inhibition (PMID:15831496)
• analysis of SPCA1 and SPCA2 isoenzymes by steady-state and transient kinetic analyses (PMID:16332677)
• ATP2C2 modulates phonological short-term memory in language impairment. (PMID:19646677)
• Findings reveal a signaling pathway in which the Orai1-SPCA2 complex elicits constitutive store-independent Ca(2+) signaling that promotes tumorigenesis. (PMID:20887894)
• Supporting a more general neurocognition role of ATP2C2 is the previous association of ATP2C2 with attention deficit hyperactivity disorder, a condition commonly comorbid with dyslexia and language impairment. (PMID:25448322)
• The extract was found to comprise mainly primary fatty acid amides (PFAAs) by NMR analysis. Individual PFAAs, especially oleamide and linoleamide, almost completely inhibited hSPCA2 activity with IC50 values of 7.5 muM and 3.8 muM, respectively. (PMID:27297103)
• we found that SPCA2-transfected cells display a higher number of cells entering S phase. Altogether, our results point at the important role of SPCA2 in regulation of cell cycle in cancer cells (PMID:27316461)
• Orai1-mediated Ca(2+)-influx and SPCA2-mediated Ca(2+) uptake activity into the Golgi/secretory pathway might be coupled possibly in a microdomain. This channel/pump complex may efficiently transfer Ca(2+) into the secretory pathway, which might play a role in SPCA2-expressing secretory cells, such as mammary gland during lactation. (PMID:27692665)
• The Secretory Pathway Ca(2+) -ATPases SPCA1 and SPCA2 are strongly induced under osteogenic conditions that elicit microcalcifications. SPCA gene expression is significantly elevated in breast cancer subtypes that are associated with microcalcifications. (PMID:28618103)
• In total, four independent SNPs within DYX1C1 and ATP2C2 were found to be associated with MMR stronger than expected from multiple testing. To explore potential pathomechanisms, we annotated these variants with functional data including tissue-specific expression analysis and eQTLs. (PMID:29201552)
• The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within ATP2C2 that associated with age of first cannabis use. (PMID:30003630)
• Original association of ion transporters mediates the ECM-induced breast cancer cell survival: Kv10.1-Orai1-SPCA2 partnership. (PMID:30718673)
• Low SPCA2 expression is associated with Epithelial-Mesenchymal Transition in Breast Cancer. (PMID:31076498)
• SPCA2C influences Ca(2+) homeostasis through multiple mechanisms, some of which are independent of Orai1, suggesting novel and possibly cell-specific Ca(2+) regulation. (PMID:31676354)
• A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures. (PMID:33864365)
• ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer. (PMID:33936088)
• Secretory pathway Ca(2+)-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry. (PMID:35063802)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp1a3a	ENSDARG00000018259
danio_rerio	atp1a3b	ENSDARG00000104139
mus_musculus	Atp2c2	ENSMUSG00000034112
rattus_norvegicus	Atp2c2	ENSRNOG00000049334
drosophila_melanogaster	anne	FBGN0052000
drosophila_melanogaster	SPoCk	FBGN0052451
drosophila_melanogaster	CG45062	FBGN0266432
drosophila_melanogaster	CG45063	FBGN0266433
caenorhabditis_elegans		WBGENE00000834
caenorhabditis_elegans	pmr-1	WBGENE00004063
caenorhabditis_elegans		WBGENE00012341
caenorhabditis_elegans		WBGENE00015338
caenorhabditis_elegans		WBGENE00015660

Paralogs (21): ATP2C1 (ENSG00000017260), ATP1A2 (ENSG00000018625), ATP2B4 (ENSG00000058668), ATP2B3 (ENSG00000067842), ATP2B1 (ENSG00000070961), ATP2A3 (ENSG00000074370), ATP12A (ENSG00000075673), ATP1A3 (ENSG00000105409), ATP4A (ENSG00000105675), ATP13A1 (ENSG00000105726), ATP7B (ENSG00000123191), ATP13A4 (ENSG00000127249), ATP1A4 (ENSG00000132681), ATP13A3 (ENSG00000133657), ATP2B2 (ENSG00000157087), ATP13A2 (ENSG00000159363), ATP1A1 (ENSG00000163399), ATP7A (ENSG00000165240), ATP2A2 (ENSG00000174437), ATP13A5 (ENSG00000187527), ATP2A1 (ENSG00000196296)

Protein

Protein identifiers

Calcium-transporting ATPase type 2C member 2 — O75185 (reviewed: O75185)

Alternative names: Ca(2+)/Mn(2+)-ATPase 2C2, Secretory pathway Ca(2+)-transporting ATPase type 2

All UniProt accessions (2): O75185, H3BS90

UniProt curated annotations — full annotation on UniProt →

Function. ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway. Within a catalytic cycle, acquires Ca(2+) or Mn(2+) ions on the cytoplasmic side of the membrane and delivers them to the lumenal side. The transfer of ions across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state. Induces Ca(2+) influx independently of its ATP-driven pump function. At the basolateral membrane of mammary epithelial cells, interacts with Ca(2+) channel ORAI1 and mediates Ca(2+) entry independently of the Ca(2+) content of endoplasmic reticulum or Golgi stores. May facilitate transepithelial transport of large quantities of Ca(2+) for milk secretion via activation of Ca(2+) influx channels at the plasma membrane and active Ca(2+) transport at the Golgi apparatus.

Subunit / interactions. Interacts (via N-terminus) with ORAI1 (via N- and C-termini); this interaction regulates Ca(2+) influx at the plasma membrane.

Subcellular location. Golgi apparatus. trans-Golgi network membrane. Cell membrane. Basolateral cell membrane.

Tissue specificity. Highly expressed in the gastrointestinal and respiratory tracts, prostate, thyroid, salivary, and mammary glands. Expressed in colon epithelial cells (at protein level). Expressed in brain and testis (at protein level).

Similarity. Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIA subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
O75185-1	1	yes
O75185-2	2
O75185-3	3

RefSeq proteins (3): NP_001273456, NP_001278383, NP_055676* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001757	P_typ_ATPase	Family
IPR004014	ATPase_P-typ_cation-transptr_N	Domain
IPR006068	ATPase_P-typ_cation-transptr_C	Domain
IPR006413	P-type_ATPase_IIA_PMR1	Family
IPR008250	ATPase_P-typ_transduc_dom_A_sf	Homologous_superfamily
IPR018303	ATPase_P-typ_P_site	PTM
IPR023214	HAD_sf	Homologous_superfamily
IPR023298	ATPase_P-typ_TM_dom_sf	Homologous_superfamily
IPR023299	ATPase_P-typ_cyto_dom_N	Homologous_superfamily
IPR036412	HAD-like_sf	Homologous_superfamily
IPR044492	P_typ_ATPase_HD_dom	Domain
IPR059000	ATPase_P-type_domA	Domain

Pfam: PF00122, PF00689, PF00690, PF13246

Enzyme classification (BRENDA):

• EC 7.2.2.10 — P-type Ca2+ transporter (BRENDA: 47 organisms, 90 substrates, 341 inhibitors, 34 Km, 18 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CA2+	—	11
ATP	—	6
CA2+/CIS	0.0007–0.0013	3
CA2+[SIDE 1]	0.0002–0.0003	2
SR2+	0.015–0.035	2
UTP	—	1

Catalyzed reactions (Rhea), 2 shown:

• Ca(2+)(in) + ATP + H2O = Ca(2+)(out) + ADP + phosphate + H(+) (RHEA:18105)
• Mn(2+)(in) + ATP + H2O = Mn(2+)(out) + ADP + phosphate + H(+) (RHEA:66820)

UniProt features (49 total): topological domain 11, transmembrane region 10, binding site 8, sequence variant 5, sequence conflict 5, modified residue 3, splice variant 2, mutagenesis site 2, chain 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75185-F1	81.13	0.27

Functional residue map

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

Catalytic / active sites (1): 379 (4-aspartylphosphate intermediate)

Ligand- & substrate-binding residues (8): 332; 333; 335; 337; 674; 678; 768; 772

Post-translational modifications (3): 264, 267, 268

Mutagenesis-validated functional residues (2):

Position	Phenotype
379	loss of calcium-dependent atpase activity. has no effect on trafficking to the plasma membrane.
772	loss of calcium-dependent atpase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 136 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOZGIT_ESR1_TARGETS_DN, GOBP_MAMMARY_GLAND_EPITHELIUM_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_MONOATOMIC_CATION_TRANSPORT, BROWNE_HCMV_INFECTION_48HR_DN, GOCC_TRANS_GOLGI_NETWORK, GOBP_CALCIUM_ION_IMPORT, GOBP_POSITIVE_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, GOBP_REGULATION_OF_CALCIUM_ION_IMPORT, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_MAMMARY_GLAND_DEVELOPMENT

GO Biological Process (9): manganese ion transport (GO:0006828), intracellular calcium ion homeostasis (GO:0006874), mammary gland epithelium development (GO:0061180), calcium ion transmembrane transport (GO:0070588), protein localization to plasma membrane (GO:0072659), positive regulation of calcium ion import (GO:0090280), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), manganese ion transmembrane transport (GO:0071421)

GO Molecular Function (8): P-type calcium transporter activity (GO:0005388), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), metal ion binding (GO:0046872), P-type manganese transporter activity (GO:0140613), nucleotide binding (GO:0000166), transporter activity (GO:0005215), protein binding (GO:0005515)

GO Cellular Component (10): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), basolateral plasma membrane (GO:0016323), cytoplasmic vesicle (GO:0031410), trans-Golgi network membrane (GO:0032588), perinuclear region of cytoplasm (GO:0048471), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
monoatomic cation transmembrane transport	2
P-type ion transporter activity	2
ATPase-coupled monoatomic cation transmembrane transporter activity	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
transition metal ion transport	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
mammary gland development	1
epithelium development	1
calcium ion transport	1
protein localization to membrane	1
protein localization to cell periphery	1
positive regulation of calcium ion transport	1
calcium ion import	1
regulation of calcium ion import	1
transport	1
metal ion transport	1
manganese ion transport	1
calcium ion transmembrane transporter activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
cation binding	1
manganese ion transmembrane transporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
membrane	1
cell periphery	1
plasma membrane	1
cytoplasmic side of membrane	1
basal plasma membrane	1
plasma membrane region	1

Protein interactions and networks

STRING

1628 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP2C2	CMIP	Q8IY22	943
ATP2C2	ORAI1	Q96D31	850
ATP2C2	F7	P08709	817
ATP2C2	DNAAF4	Q8WXU2	748
ATP2C2	DCDC2	Q9UHG0	745
ATP2C2	KIAA0319	Q5VV43	701
ATP2C2	NFXL1	Q6ZNB6	690
ATP2C2	STIM1	Q13586	635
ATP2C2	ORAI3	Q9BRQ5	628
ATP2C2	CNTNAP2	Q9UHC6	623
ATP2C2	CEBPD	P49716	604
ATP2C2	GCFC2	P16383	577
ATP2C2	NAGPA	Q9UK23	574
ATP2C2	FOXP2	O15409	573
ATP2C2	MRPL19	P49406	567

IntAct

12 interactions, top by confidence:

A	B	Type	Score
ATP2C2	ORAI1	psi-mi:“MI:0915”(physical association)	0.610
ORAI1	ATP2C2	psi-mi:“MI:0915”(physical association)	0.610
ORAI1	ATP2C2	psi-mi:“MI:0403”(colocalization)	0.610
ATP2C2	LMNA	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (161): LMNA (Proximity Label-MS), ATP2C2 (Negative Genetic), ATP2C2 (Affinity Capture-Western), CKAP4 (Proximity Label-MS), SLC3A2 (Proximity Label-MS), TOR1AIP1 (Proximity Label-MS), HK1 (Proximity Label-MS), STX5 (Proximity Label-MS), TMX1 (Proximity Label-MS), PTPN1 (Proximity Label-MS), CCDC47 (Proximity Label-MS), UBXN4 (Proximity Label-MS), FAM114A2 (Proximity Label-MS), LEMD3 (Proximity Label-MS), LBR (Proximity Label-MS)

ESM2 similar proteins: A0A0P0X004, A3AWA4, A7L9Z8, B9DFX7, O04130, O22218, O23087, O43108, O49485, O59666, O64806, O75185, O81108, P0CW77, P0CW78, P35315, P38995, P54209, P54678, P57709, P92939, Q2QMX9, Q2QY12, Q2RAS0, Q37145, Q42883, Q4WND5, Q5R5K5, Q64568, Q65X71, Q6ATV4, Q6H7M3, Q7X8B5, Q7XB51, Q7XEK4, Q8H384, Q8R4C1, Q8RUN1, Q93Z53, Q9LF79

Diamond homologs: A0A143ZZK9, A2VDL6, A7L9Z8, B9QMJ0, D2WKD8, O13397, O13398, O14983, O23087, O34431, O46674, O55143, O75185, O77696, P04074, P04191, P05023, P06685, P07038, P09572, P09626, P09627, P11507, P11607, P11718, P12522, P13585, P13586, P16615, P17326, P18596, P18907, P19156, P20431, P20647, P20648, P22189, P22700, P25489, P27112

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	292
Likely benign	58
Benign	33

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
975044	Single allele	Likely pathogenic

SpliceAI

4550 predictions. Top by Δscore:

Variant	Effect	Δscore
16:84368706:G:GT	donor_gain	1.0000
16:84368713:TGG:T	donor_loss	1.0000
16:84368714:GGTG:G	donor_loss	1.0000
16:84368715:G:GG	donor_gain	1.0000
16:84368715:GTG:G	donor_loss	1.0000
16:84368716:T:A	donor_loss	1.0000
16:84398565:G:GT	donor_gain	1.0000
16:84398608:GT:G	donor_gain	1.0000
16:84398610:G:GG	donor_gain	1.0000
16:84405242:CAGG:C	donor_loss	1.0000
16:84405244:GG:G	donor_loss	1.0000
16:84405245:G:GA	donor_loss	1.0000
16:84405246:T:G	donor_loss	1.0000
16:84408403:A:AG	acceptor_gain	1.0000
16:84408404:G:GA	acceptor_gain	1.0000
16:84408404:GT:G	acceptor_gain	1.0000
16:84408404:GTT:G	acceptor_gain	1.0000
16:84408404:GTTT:G	acceptor_gain	1.0000
16:84408404:GTTTA:G	acceptor_gain	1.0000
16:84408495:G:GG	donor_gain	1.0000
16:84408495:GTGAG:G	donor_loss	1.0000
16:84408496:T:A	donor_loss	1.0000
16:84408497:GAGT:G	donor_loss	1.0000
16:84410567:GGCA:G	acceptor_gain	1.0000
16:84415471:T:G	acceptor_gain	1.0000
16:84422385:CCTAG:C	acceptor_loss	1.0000
16:84422386:CTA:C	acceptor_loss	1.0000
16:84422387:TAGGT:T	acceptor_loss	1.0000
16:84422388:A:AG	acceptor_gain	1.0000
16:84422388:AGGT:A	acceptor_loss	1.0000

AlphaMissense

6190 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:84415527:T:A	V187D	0.996
16:84415571:G:C	A202P	0.996
16:84415572:C:A	A202E	0.996
16:84405193:T:A	N92K	0.995
16:84405193:T:G	N92K	0.995
16:84415524:T:C	L186P	0.995
16:84459184:A:C	S738R	0.995
16:84459186:C:A	S738R	0.995
16:84459186:C:G	S738R	0.995
16:84415533:G:A	G189D	0.994
16:84422629:G:A	G259R	0.994
16:84422629:G:C	G259R	0.994
16:84422630:G:A	G259E	0.994
16:84422636:T:A	V261E	0.994
16:84454854:G:T	G673W	0.994
16:84415581:G:C	R205P	0.993
16:84422629:G:T	G259W	0.993
16:84425800:A:C	S329R	0.993
16:84439166:C:A	S329R	0.993
16:84439166:C:G	S329R	0.993
16:84446380:T:C	F485L	0.993
16:84446382:C:A	F485L	0.993
16:84446382:C:G	F485L	0.993
16:84405171:G:C	R85P	0.992
16:84415533:G:T	G189V	0.992
16:84422400:T:C	L212P	0.992
16:84422449:A:C	K228N	0.992
16:84422449:A:T	K228N	0.992
16:84459175:T:C	F735L	0.992
16:84459177:C:A	F735L	0.992

dbSNP variants (sampled 300 via entrez): RS1000019101 (16:84409072 T>C,G), RS1000053155 (16:84435577 G>A,C), RS1000064314 (16:84381437 T>C), RS1000085766 (16:84435361 T>C), RS1000122833 (16:84388661 T>G), RS1000133476 (16:84412094 G>A,C), RS1000135622 (16:84393820 G>C), RS1000145290 (16:84451141 G>T), RS1000156780 (16:84377863 C>A,G,T), RS1000169420 (16:84445017 G>GA), RS1000259386 (16:84418766 G>T), RS1000265893 (16:84439107 C>G,T), RS1000266277 (16:84405709 C>G), RS1000281808 (16:84366887 G>A), RS1000285918 (16:84455714 C>T)

Disease associations

OMIM: gene MIM:613082 | disease phenotypes: MIM:265380

GenCC curated gene-disease

Disease	Classification	Inheritance
speech disorder	Limited	Autosomal dominant

Mondo (2): alveolar capillary dysplasia with misalignment of pulmonary veins (MONDO:0009934), speech disorder (MONDO:0004730)

Orphanet (1): Congenital alveolar capillary dysplasia (Orphanet:210122)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000246_14	Attention deficit hyperactivity disorder	8.000000e-07
GCST001737_5	Chronic obstructive pulmonary disease-related biomarkers	9.000000e-13
GCST005727_5	Peanut allergy (parent-of-origin effect)	8.000000e-06
GCST009391_1116	Metabolite levels	4.000000e-07
GCST010483_3	Cardiovascular death, myocardial infarction or stroke in response to clopidogrel treatment	3.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005081	surfactant protein D measurement
EFO:0005939	parental genotype effect measurement
EFO:0007017	peanut allergy measurement
EFO:0010523	phosphoglyceric acid measurement
EFO:0006919	cardiovascular event measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D013064	Speech Disorders	C10.597.606.150.500.800; C23.888.592.604.150.500.800
C536590	Alveolar capillary dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — P2B P-type ATPases: Ca²⁺-ATPases

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation, affects cotreatment	1
trichostatin A	increases expression	1
sodium arsenite	increases abundance, increases expression	1
aflatoxin B2	decreases methylation	1
hydroquinone	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	increases abundance, increases expression	1
Endosulfan	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Formaldehyde	decreases expression	1
Methotrexate	decreases expression	1
Silicon Dioxide	decreases expression	1
Aflatoxin B1	decreases methylation	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00732537	PHASE4	COMPLETED	Inhaled Nitric Oxide by Oxygen Hood in Neonates
NCT04323085	PHASE2	UNKNOWN	Speech-in-Noise Treatments for Hypophonia in Parkinson’s Disease
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT02909088	PHASE2/PHASE3	UNKNOWN	Efficacy and Tolerability of Ecopipam in Adults With Childhood Onset Fluency Disorder (Stuttering).
NCT00001167	Not specified	COMPLETED	Ultrasound Evaluation of Tongue Movements in Speech and Swallowing
NCT00001218	Not specified	COMPLETED	Development of Normative Ultrasound Databases of Tongue Surface Configuration
NCT00001448	Not specified	COMPLETED	The Effect of Oral Candidiasis on the Speech Production, Feeding Skills, and Self-Concept of Children and Adolescents With Symptomatic HIV Infection
NCT00001551	Not specified	COMPLETED	Characteristics of Idiopathic Familial Speech Disorders
NCT00125216	Not specified	COMPLETED	Evaluation of the Effects of Response Elaboration Training for Aphasia
NCT00125242	Not specified	COMPLETED	Word-Retrieval Treatment for Aphasia: Semantic Feature Analysis
NCT01180309	Not specified	COMPLETED	Lingual Frenum and Articulation of Phonemes
NCT02288598	Not specified	COMPLETED	Enhancing Speech Fluency With Non-invasive Brain Stimulation in Developmental Stuttering
NCT02416856	Not specified	COMPLETED	Brain Connectivity Supporting Language Recovery in Aphasia
NCT02490826	Not specified	COMPLETED	Table to Tablet (T2T): A Novel Intervention Framework for Children With Speech Sound Disorders
NCT02554513	Not specified	COMPLETED	Apraxia of Speech: Comparison of EPG Treatment (Tx) and Sound Production Treatment (SPT)
NCT02752425	Not specified	COMPLETED	Visual Feedback of Tongue by Ultrasound Echography for Speech Trouble Rehabilitation
NCT03663972	Not specified	COMPLETED	Age-related Correlates of Treatment for Late-acquired Sounds
NCT04009811	Not specified	COMPLETED	A New Membrane Obturator Prothesis Concept for Soft Palate Defects
NCT04026581	Not specified	COMPLETED	Real World Testing of a Brain-Computer Interface
NCT04117360	Not specified	RECRUITING	Orthognathic Speech Pathology: Phonetic Contrasts of Patients With Dental Discrepancies Pre- and Post-Treatment Analyses
NCT04528147	Not specified	UNKNOWN	Yi Jin Jing Tiger Roaring Speech Rehabilitation With Real-Time Feedback Technique for PD
NCT04690166	Not specified	COMPLETED	Validation of the Turkish Translation of the London Speech Evaluation Scale
NCT04762043	Not specified	COMPLETED	MyoVoice to Restore Natural, Hands-free Communication to Individuals With Vocal Impairments
NCT04966689	Not specified	COMPLETED	The Effect of Combined Speech and Music-therapy on the Speech Characteristics of People With Parkinson’s Disease (PD)
NCT05369663	Not specified	COMPLETED	Personal Protective Equipment Effects
NCT05489965	Not specified	RECRUITING	Gender Disparities in Voice Outcomes After Tracheoesophageal Puncture in Total Laryngectomy Patients (UC Davis)
NCT05695131	Not specified	RECRUITING	Clinical Feasibility & Validation of the Virtual Reality GlenxRose Speech-Language Therapies
NCT05741853	Not specified	RECRUITING	Cognitive Reserve and Response to Speech-Language Intervention in Bilingual Speakers With Primary Progressive Aphasia
NCT05876247	Not specified	UNKNOWN	Articulatory Adaptation Following Oral Cancer Treatment
NCT06114914	Not specified	UNKNOWN	TapTalkTest Project:Development of a Non-invasive Screening Test to Detect Risk of Alzheimer’s Disease Pathology
NCT06443073	Not specified	RECRUITING	The Mere-measurement Effect of Patient-reported Outcomes
NCT06633874	Not specified	COMPLETED	Smart Computing Models, Sensors, and Early Diagnostic Speech and Language Deficiencies Indicators in Child Communication
NCT06874322	Not specified	RECRUITING	Voiceitt for People With Impairments in Speech
NCT06913517	Not specified	ACTIVE_NOT_RECRUITING	Effect of Hearing Aid Versus Cochlear Implant on Hearing and Speech Recognition in Children
NCT07264036	Not specified	RECRUITING	Velopharyngeal Dysfunction in Head & Neck Cancer Patients, Pilot Study
NCT07330687	Not specified	COMPLETED	Neural Changes After Speech Therapy in Patients With Cleft Palate: A Brain Imaging Study
NCT04328636	PHASE1/PHASE2	COMPLETED	Nebulized MgSO4 in Persistent Pulmonary Hypertension of Newborn