SLC9C1

Chr 3

solute carrier family 9 member C1

Also known as: NHE, NHE-10, SLC9A10, sperm-NHE

NCBI Gene: 285335 ENSG00000172139 UniProt: Q4G0N8 OMIM: 612738

This protein functions as a sperm-specific sodium/potassium-proton antiporter that regulates intracellular pH in spermatozoa and is required for sperm motility and male fertility. Mutations in SLC9C1 cause male infertility due to defective sperm motility, inherited in an autosomal recessive pattern. The gene is extremely intolerant to loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

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. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.77

Clinical Summary— SLC9C1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

136 VUS of 167 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.77LOEUF

pLI 0.000

Z-score 3.01

OE 0.57 (0.43–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.06Z-score

OE missense 0.99 (0.93–1.06)

570 obs / 574.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.43–0.77)

0≤0.351.4

Missense OE?0.99 (0.93–1.06)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 33 / 57.7Missense obs/exp: 570 / 574.1Syn Z: -0.15

This gene — mechanism propensity

0.82top 10%

GOF

0.77top 25%

LOF

0.1399th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

167 submitted variants in ClinVar

ClinVar

Classification Summary

VUS136

Likely Benign16

Benign2

136

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	136	0	0	136
Likely Benign	13	0	3	16
Benign	0	1	1	2
Total	149	1	4	154

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

18 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap SLC9C1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →