SLC9C1

Summary

SLC9C1 (solute carrier family 9 member C1, HGNC:31401) is a protein-coding gene on chromosome 3q13.2, encoding Solute carrier family 9 member C1 (Q4G0N8). Sperm-specific solute carrier involved in intracellular pH regulation of spermatozoa.

Predicted to enable potassium:proton antiporter activity and sodium:proton antiporter activity. Predicted to be involved in potassium ion transmembrane transport; regulation of intracellular pH; and sodium ion import across plasma membrane. Predicted to act upstream of or within flagellated sperm motility. Predicted to be located in membrane and motile cilium. Predicted to be active in plasma membrane.

Source: NCBI Gene 285335 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 167 total
• MANE Select transcript: NM_183061

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31401
Approved symbol	SLC9C1
Name	solute carrier family 9 member C1
Location	3q13.2
Locus type	gene with protein product
Status	Approved
Aliases	NHE
Ensembl gene	ENSG00000172139
Ensembl biotype	protein_coding
OMIM	612738
Entrez	285335

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 nonsense_mediated_decay

ENST00000305815, ENST00000467397, ENST00000471295, ENST00000486574, ENST00000487372

RefSeq mRNA: 2 — MANE Select: NM_183061 NM_001320531, NM_183061

CCDS: CCDS33817, CCDS82818

Canonical transcript exons

ENST00000305815 — 29 exons

Exon	Start	End
ENSE00001157253	112208178	112208373
ENSE00001175621	112243995	112244076
ENSE00001200195	112262924	112263098
ENSE00001200197	112264200	112264343
ENSE00001200198	112266238	112266340
ENSE00001386738	112204218	112204403
ENSE00001498081	112140898	112141281
ENSE00001498085	112269916	112270077
ENSE00001498086	112274897	112275025
ENSE00001498087	112277695	112277860
ENSE00001952047	112294093	112294216
ENSE00003466931	112179531	112179701
ENSE00003469904	112168877	112169062
ENSE00003490498	112182133	112182258
ENSE00003490771	112169197	112169328
ENSE00003500618	112217442	112217561
ENSE00003524954	112167221	112167347
ENSE00003530010	112221128	112221225
ENSE00003541958	112154997	112155049
ENSE00003563036	112239840	112240006
ENSE00003565112	112199321	112199469
ENSE00003565380	112280683	112280783
ENSE00003584304	112202250	112202399
ENSE00003596373	112278729	112278857
ENSE00003602183	112200711	112200762
ENSE00003611348	112151857	112151963
ENSE00003614804	112180564	112180662
ENSE00003625875	112231361	112231486
ENSE00003674515	112286704	112286878

Expression profiles

Bgee: expression breadth broad, 86 present calls, max score 79.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2260 / max 43.0908, expressed in 70 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43731	0.1963	60
43732	0.0297	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.82	gold quality
body of pancreas	UBERON:0001150	68.28	gold quality
testis	UBERON:0000473	67.70	gold quality
left testis	UBERON:0004533	66.35	gold quality
right testis	UBERON:0004534	65.60	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.39	gold quality
pancreas	UBERON:0001264	63.34	gold quality
skin of abdomen	UBERON:0001416	62.04	gold quality
zone of skin	UBERON:0000014	61.69	gold quality
skin of leg	UBERON:0001511	61.36	gold quality
heart left ventricle	UBERON:0002084	60.73	gold quality
apex of heart	UBERON:0002098	59.64	gold quality
left lobe of thyroid gland	UBERON:0001120	57.14	gold quality
islet of Langerhans	UBERON:0000006	56.62	gold quality
thyroid gland	UBERON:0002046	56.61	gold quality
right lobe of thyroid gland	UBERON:0001119	55.28	gold quality
heart	UBERON:0000948	55.09	gold quality
calcaneal tendon	UBERON:0003701	55.03	gold quality
body of stomach	UBERON:0001161	54.97	gold quality
stomach	UBERON:0000945	54.61	gold quality
rectum	UBERON:0001052	53.61	gold quality
right uterine tube	UBERON:0001302	52.52	gold quality
gall bladder	UBERON:0002110	52.07	gold quality
duodenum	UBERON:0002114	51.80	gold quality
metanephros cortex	UBERON:0010533	51.77	gold quality
adrenal tissue	UBERON:0018303	51.18	gold quality
cortex of kidney	UBERON:0001225	50.70	gold quality
upper lobe of left lung	UBERON:0008952	50.58	gold quality
lung	UBERON:0002048	50.47	gold quality
kidney	UBERON:0002113	50.37	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

32 targeting SLC9C1, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-1248	98.47	67.54	1314
HSA-MIR-135A-2-3P	98.40	66.74	442
HSA-MIR-135B-3P	98.40	67.35	426
HSA-MIR-561-5P	98.25	68.13	1365

Literature-anchored findings (GeneRIF, showing 2)

• this review outlines the contribution of NHE to chronic complications of diabetes mellitus, such as diabetic nephropathy; diabetic cardiomyopathy.[review] (PMID:23000155)
• The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility. (PMID:33462806)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Slc9c1	ENSMUSG00000033210
rattus_norvegicus	Slc9c1	ENSRNOG00000022007
drosophila_melanogaster	Nhe3	FBGN0028703
drosophila_melanogaster	Nhe2	FBGN0040297
caenorhabditis_elegans		WBGENE00003730
caenorhabditis_elegans		WBGENE00003732
caenorhabditis_elegans		WBGENE00003733
caenorhabditis_elegans		WBGENE00003734

Paralogs (10): SLC9A7 (ENSG00000065923), SLC9A3 (ENSG00000066230), SLC9A1 (ENSG00000090020), SLC9A2 (ENSG00000115616), SLC9A5 (ENSG00000135740), SLC9C2 (ENSG00000162753), SLC9A4 (ENSG00000180251), SLC9A9 (ENSG00000181804), SLC9A8 (ENSG00000197818), SLC9A6 (ENSG00000198689)

Protein

Protein identifiers

Solute carrier family 9 member C1 — Q4G0N8 (reviewed: Q4G0N8)

Alternative names: Na(+)/H(+) exchanger 10, Sodium/hydrogen exchanger 10, Solute carrier family 9 member 10, Sperm-specific Na(+)/H(+) exchanger

All UniProt accessions (4): Q4G0N8, A0AAA9YHL5, C9J3M6, F8WCJ0

UniProt curated annotations — full annotation on UniProt →

Function. Sperm-specific solute carrier involved in intracellular pH regulation of spermatozoa. Required for sperm motility and fertility. Involved in sperm cell hyperactivation, a step needed for sperm motility which is essential late in the preparation of sperm for fertilization. Required for the expression and bicarbonate regulation of the soluble adenylyl cyclase (sAC).

Subunit / interactions. Interacts with soluble adenylyl cyclase (sAC).

Subcellular location. Cell projection. Cilium. Flagellum membrane.

Tissue specificity. Sperm.

Domain organisation. The ion transport-like region is related to the membrane segments of voltage-gated ion channels. Its function is unknown.

Similarity. Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q4G0N8-1	1	yes
Q4G0N8-2	2

RefSeq proteins (2): NP_001307460, NP_898884* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000595	cNMP-bd_dom	Domain
IPR005821	Ion_trans_dom	Domain
IPR006153	Cation/H_exchanger_TM	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018422	Cation/H_exchanger_CPA1	Family
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR027359	Volt_channel_dom_sf	Homologous_superfamily

Pfam: PF00027, PF00520, PF00999

UniProt features (52 total): topological domain 18, transmembrane region 17, sequence variant 9, region of interest 3, sequence conflict 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9YDF	X-RAY DIFFRACTION	2.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4G0N8-F1	74.66	0.09

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 71 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_MALE_GAMETE_GENERATION, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOMF_PROTON_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOBP_REGULATION_OF_PH, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_IMPORT_INTO_CELL, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT, GOCC_MOTILE_CILIUM, GOBP_HOMEOSTATIC_PROCESS

GO Biological Process (12): spermatogenesis (GO:0007283), cell differentiation (GO:0030154), flagellated sperm motility (GO:0030317), regulation of intracellular pH (GO:0051453), potassium ion transmembrane transport (GO:0071805), sodium ion import across plasma membrane (GO:0098719), monoatomic ion transport (GO:0006811), monoatomic cation transport (GO:0006812), sodium ion transport (GO:0006814), sodium ion transmembrane transport (GO:0035725), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600)

GO Molecular Function (4): monoatomic ion channel activity (GO:0005216), sodium:proton antiporter activity (GO:0015385), potassium:proton antiporter activity (GO:0015386), antiporter activity (GO:0015297)

GO Cellular Component (5): plasma membrane (GO:0005886), motile cilium (GO:0031514), cilium (GO:0005929), membrane (GO:0016020), cell projection (GO:0042995)

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
monoatomic cation transmembrane transport	3
transport	2
metal cation:proton antiporter activity	2
cellular anatomical structure	2
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
regulation of pH	1
intracellular monoatomic cation homeostasis	1
regulation of biological quality	1
potassium ion transport	1
sodium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
monoatomic ion transport	1
metal ion transport	1
sodium ion transport	1
cellular process	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
sodium ion transmembrane transporter activity	1
solute:potassium antiporter activity	1
secondary active transmembrane transporter activity	1
membrane	1
cell periphery	1
cilium	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

696 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC9C1	SLC9A1	P19634	925
SLC9C1	ADCY10	Q96PN6	752
SLC9C1	LGALS1	P09382	717
SLC9C1	SLC9B1	Q4ZJI4	707
SLC9C1	KCNU1	A8MYU2	687
SLC9C1	SLC9A5	Q14940	645
SLC9C1	SLC9B2	Q86UD5	637
SLC9C1	SLC9A6	Q92581	598
SLC9C1	CATSPER1	Q8NEC5	582
SLC9C1	HVCN1	Q96D96	581
SLC9C1	SLC9A9	Q8IVB4	543
SLC9C1	SLC9A8	Q9Y2E8	530
SLC9C1	CATSPER3	Q86XQ3	525
SLC9C1	NOMO2	Q5JPE7	507
SLC9C1	NOMO3	P69849	506

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SPAG5	PLK1	psi-mi:“MI:0914”(association)	0.510
SLC9C1	PSMD12	psi-mi:“MI:0914”(association)	0.350
SLC9C1	SPAG5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): SPAG5 (Affinity Capture-MS), SLC9C1 (Affinity Capture-MS), ADRM1 (Affinity Capture-MS), AMFR (Affinity Capture-MS), BAG2 (Affinity Capture-MS), BAG5 (Affinity Capture-MS), DNAJB1 (Affinity Capture-MS), HERC3 (Affinity Capture-MS), NLRX1 (Affinity Capture-MS), NPLOC4 (Affinity Capture-MS), PPM1L (Affinity Capture-MS), PSMA3 (Affinity Capture-MS), PSMB1 (Affinity Capture-MS), PSMB3 (Affinity Capture-MS), PSMC6 (Affinity Capture-MS)

ESM2 similar proteins: A1Z7R6, A6NIM6, A6QNW6, A9JTG4, A9X4U2, E1BPQ3, F4I9E1, F4KIL8, F5H094, G3V0H7, O35913, O80436, O94911, Q497L8, Q497L9, Q4G0N8, Q4R445, Q5BIZ0, Q5BK75, Q5TAH2, Q5XGZ9, Q68EU6, Q6DBX0, Q6TAC4, Q6UJY2, Q7SXB7, Q86UG4, Q8C0X7, Q8CBB2, Q8IUA7, Q8K440, Q8K441, Q8K442, Q8K449, Q8N139, Q8R0C3, Q8R0S9, Q8WWZ4, Q924V4, Q96RN1

Diamond homologs: A2APX8, A2ASI5, B1AWN6, B1AYL1, D0E0C2, F1LQQ7, O08562, O42398, O46669, O73706, O73707, O88420, O88457, P02719, P04774, P04775, P08104, P0DMA5, P15389, P15390, P35498, P35499, P35500, Q01118, Q05973, Q14524, Q15858, Q20JQ7, Q28371, Q28644, Q2XVR3, Q2XVR4, Q2XVR5, Q2XVR6, Q2XVR7, Q4G0N8, Q62205, Q62968, Q6QIY3, Q99250

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	136
Likely benign	15
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

4276 predictions. Top by Δscore:

Variant	Effect	Δscore
3:112141293:G:T	acceptor_gain	1.0000
3:112154995:ACCT:A	donor_gain	1.0000
3:112154996:CCTC:C	donor_gain	1.0000
3:112154998:T:TA	donor_gain	1.0000
3:112199040:A:AC	donor_gain	1.0000
3:112199041:C:CC	donor_gain	1.0000
3:112199316:CTTA:C	donor_loss	1.0000
3:112199318:TA:T	donor_loss	1.0000
3:112199319:A:C	donor_loss	1.0000
3:112199320:C:CG	donor_loss	1.0000
3:112199466:TAGC:T	acceptor_gain	1.0000
3:112199470:C:CA	acceptor_loss	1.0000
3:112199470:C:CC	acceptor_gain	1.0000
3:112200760:CAT:C	acceptor_gain	1.0000
3:112231359:A:AC	donor_gain	1.0000
3:112231360:C:CC	donor_gain	1.0000
3:112239838:A:AC	donor_gain	1.0000
3:112239839:C:CA	donor_loss	1.0000
3:112239839:C:CC	donor_gain	1.0000
3:112266236:A:AC	donor_gain	1.0000
3:112266237:C:CG	donor_gain	1.0000
3:112266237:CT:C	donor_gain	1.0000
3:112141277:CTTTC:C	acceptor_gain	0.9900
3:112141281:CCTAA:C	acceptor_gain	0.9900
3:112141285:A:C	acceptor_gain	0.9900
3:112141292:C:CT	acceptor_gain	0.9900
3:112141962:T:TA	donor_gain	0.9900
3:112154992:TTTAC:T	donor_loss	0.9900
3:112154993:TTACC:T	donor_loss	0.9900
3:112154994:TAC:T	donor_loss	0.9900

AlphaMissense

7839 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:112270034:A:C	S219R	0.994
3:112270034:A:T	S219R	0.994
3:112270036:T:G	S219R	0.994
3:112182171:A:G	W871R	0.989
3:112182171:A:T	W871R	0.989
3:112239884:A:G	W468R	0.981
3:112239884:A:T	W468R	0.981
3:112169256:A:G	W998R	0.979
3:112169256:A:T	W998R	0.979
3:112199392:C:G	A818P	0.977
3:112239882:C:A	W468C	0.977
3:112239882:C:G	W468C	0.977
3:112179546:G:C	C968W	0.974
3:112263011:A:C	S370R	0.972
3:112263011:A:T	S370R	0.972
3:112263013:T:G	S370R	0.972
3:112264290:C:T	G311E	0.970
3:112270023:C:T	G223E	0.969
3:112221220:G:C	S526R	0.967
3:112221220:G:T	S526R	0.967
3:112221222:T:G	S526R	0.967
3:112277735:A:C	S148R	0.964
3:112277735:A:T	S148R	0.964
3:112277737:T:G	S148R	0.964
3:112270024:C:G	G223R	0.963
3:112270024:C:T	G223R	0.963
3:112208325:A:C	F613L	0.962
3:112208325:A:T	F613L	0.962
3:112208327:A:G	F613L	0.962
3:112280721:C:G	G51R	0.959

dbSNP variants (sampled 300 via entrez): RS1000014739 (3:112262863 T>C), RS1000054531 (3:112164942 C>A), RS1000079085 (3:112187332 T>C), RS1000084980 (3:112264434 T>A,C), RS1000088579 (3:112164764 T>C), RS1000094199 (3:112211563 C>T), RS1000107097 (3:112228383 T>C,G), RS1000129787 (3:112255903 C>G), RS1000157233 (3:112193797 T>C), RS1000164802 (3:112212462 A>C,G), RS1000180218 (3:112212883 C>G), RS1000250616 (3:112213078 A>T), RS1000266929 (3:112283002 A>C), RS1000285870 (3:112223548 T>A), RS1000319497 (3:112283354 G>C)

Disease associations

OMIM: gene MIM:612738 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004606_113	Eosinophil count	1.000000e-09
GCST004623_140	Neutrophil percentage of granulocytes	1.000000e-09
GCST004624_47	Sum eosinophil basophil counts	8.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count

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 — SLC9 family of sodium/hydrogen exchangers

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression, increases methylation	2
Benzo(a)pyrene	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Lactic Acid	increases expression	1
Permethrin	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TP35	HAP1 SLC9C1 (-) 1	Cancer cell line	Male
CVCL_TP36	HAP1 SLC9C1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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