Congenital secretory sodium diarrhea 8

Summary

Congenital secretory sodium diarrhea 8 (MONDO:0014808) is a disease caused by SLC9A3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: SLC9A3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital secretory sodium diarrhea 8
Mondo ID	MONDO:0014808
OMIM	616868
DOID	DOID:0060777
UMLS	C5441928
MedGen	1783137
GARD	0018261
Is cancer (heuristic)	no

Also known as: congenital secretory sodium diarrhea type 8 · congenital secretory sodium diarrhoea type 8 · DIAR8 · diarrhea 8, secretory sodium, congenital · diarrhoea 8, secretory sodium, congenital · secretory diarrhea caused by mutation in SLC9A3 · secretory diarrhoea caused by mutation in SLC9A3 · SLC9A3 secretory diarrhea · SLC9A3 secretory diarrhoea

Data availability: 34 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › diarrheal disease › congenital diarrhea › congenital sodium diarrhea › congenital secretory sodium diarrhea 8

Related subtypes (2): congenital secretory sodium diarrhea 3, syndromic congenital sodium diarrhea

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

34 retrieved; paginated sample, class counts are floors:

9 conflicting classifications of pathogenicity, 8 benign, 8 pathogenic, 4 uncertain significance, 2 pathogenic/likely pathogenic, 1 likely benign, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
224595	NM_004174.4(SLC9A3):c.932C>T (p.Ala311Val)	SLC9A3	Pathogenic	no assertion criteria provided
224596	NM_004174.4(SLC9A3):c.341TCT[3] (p.Phe117del)	SLC9A3	Pathogenic	no assertion criteria provided
224597	NM_004174.4(SLC9A3):c.1145G>A (p.Arg382Gln)	SLC9A3	Pathogenic	criteria provided, single submitter
224599	NM_004174.4(SLC9A3):c.805G>A (p.Ala269Thr)	SLC9A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224600	NM_004174.4(SLC9A3):c.782dup (p.Thr262fs)	SLC9A3	Pathogenic	no assertion criteria provided
3255340	NM_004174.4(SLC9A3):c.1446+1delinsCA	SLC9A3	Pathogenic	criteria provided, single submitter
3255341	NM_004174.4(SLC9A3):c.1052dup (p.Met352fs)	SLC9A3	Pathogenic	criteria provided, single submitter
592108	NM_004174.4(SLC9A3):c.932+1G>A	SLC9A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
986310	NM_004174.4(SLC9A3):c.1214A>G (p.Asp405Gly)	SLC9A3	Pathogenic	criteria provided, single submitter
224598	NM_004174.4(SLC9A3):c.1745del (p.Ser582fs)	SLC9A3-AS1	Pathogenic	criteria provided, single submitter
3255342	NM_004174.4(SLC9A3):c.650C>T (p.Ser217Leu)	SLC9A3	Likely pathogenic	criteria provided, single submitter
1053639	NM_004174.4(SLC9A3):c.2087A>G (p.Asn696Ser)	SLC9A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1345152	NM_004174.4(SLC9A3):c.931G>A (p.Ala311Thr)	SLC9A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1477819	NM_004174.4(SLC9A3):c.564G>A (p.Met188Ile)	SLC9A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1609114	NM_004174.4(SLC9A3):c.579G>A (p.Pro193=)	SLC9A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2628756	NM_004174.4(SLC9A3):c.818C>T (p.Ser273Leu)	SLC9A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2754916	NM_004174.4(SLC9A3):c.445G>A (p.Val149Met)	SLC9A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547876	NM_004174.4(SLC9A3):c.1814G>A (p.Arg605Gln)	SLC9A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625848	NM_004174.4(SLC9A3):c.1039G>A (p.Glu347Lys)	SLC9A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
798938	NM_004174.4(SLC9A3):c.1212T>C (p.Ile404=)	SLC9A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034058	NM_004174.4(SLC9A3):c.1862A>G (p.Gln621Arg)	SLC9A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1213686	NM_004174.4(SLC9A3):c.340G>A (p.Val114Ile)	SLC9A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806486	NM_004174.4(SLC9A3):c.1446+1G>C	SLC9A3	Uncertain significance	criteria provided, single submitter
4080121	NM_004174.4(SLC9A3):c.176C>A (p.Ala59Glu)	SLC9A3	Uncertain significance	criteria provided, single submitter
1143432	NM_004174.4(SLC9A3):c.370G>A (p.Val124Met)	SLC9A3	Likely benign	criteria provided, multiple submitters, no conflicts
1168112	NM_004174.4(SLC9A3):c.2395T>C (p.Cys799Arg)	SLC9A3	Benign	criteria provided, multiple submitters, no conflicts
1168113	NM_004174.4(SLC9A3):c.1443G>C (p.Gly481=)	SLC9A3	Benign	criteria provided, multiple submitters, no conflicts
1168114	NM_004174.4(SLC9A3):c.1356+10A>G	SLC9A3	Benign	criteria provided, multiple submitters, no conflicts
1185379	NM_004174.4(SLC9A3):c.1647+68dup	SLC9A3	Benign	criteria provided, single submitter
1185380	NM_004174.4(SLC9A3):c.1517+70A>G	SLC9A3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC9A3	Strong	Autosomal recessive	congenital secretory sodium diarrhea 8	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC9A3	Orphanet:103908	Congenital sodium diarrhea
SLC9A3	Orphanet:586	Cystic fibrosis

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC9A3	HGNC:11073	ENSG00000066230	P48764	Sodium/hydrogen exchanger 3	gencc,clinvar
SLC9A3-AS1	HGNC:40550	ENSG00000225138		SLC9A3 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC9A3	Sodium/hydrogen exchanger 3	Plasma membrane Na(+)/H(+) antiporter.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC9A3	Other/Unknown	no		NaH_exchanger, Cation/H_exchanger_TM, Na/H_exchanger_3/5
SLC9A3-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	1
mucosa of transverse colon	1
sural nerve	1
lower esophagus mucosa	1
right testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC9A3	164	tissue_specific	yes	mucosa of transverse colon, sural nerve, metanephros cortex
SLC9A3-AS1	215	ubiquitous	marker	right uterine tube, right testis, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC9A3	1,800
SLC9A3-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC9A3	P48764	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sodium/Proton exchangers	1	1268.9×	0.003	SLC9A3
R-HSA-425393	1	129.8×	0.015	SLC9A3
SLC-mediated transmembrane transport	1	59.2×	0.023	SLC9A3
Transport of small molecules	1	25.1×	0.040	SLC9A3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sodium ion import across plasma membrane	1	624.1×	0.003	SLC9A3
regulation of intracellular pH	1	601.9×	0.003	SLC9A3
monoatomic ion transport	1	156.0×	0.007	SLC9A3
potassium ion transmembrane transport	1	135.9×	0.007	SLC9A3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SLC9A3	TENAPANOR HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC9A3	3	4
SLC9A3-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TENAPANOR HYDROCHLORIDE	4	SLC9A3
TENAPANOR	4	SLC9A3
ENIPORIDE	2	SLC9A3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SLC9A3	20	Binding:18, Functional:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TENAPANOR HYDROCHLORIDE	4	SLC9A3
TENAPANOR	4	SLC9A3
ENIPORIDE	2	SLC9A3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC9A3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC9A3-AS1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC9A3-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.