Congenital diarrhea 6

Summary

Congenital diarrhea 6 (MONDO:0013825) is a disease caused by GUCY2C (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GUCY2C (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		32	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital diarrhea 6
Mondo ID	MONDO:0013825
OMIM	614616
Orphanet	314373
DOID	DOID:0060780
UMLS	C3553270
MedGen	766184
GARD	0017417
Is cancer (heuristic)	no

Also known as: congenital diarrhea caused by mutation in GUCY2C · congenital diarrhea type 6 · congenital diarrhoea caused by mutation in GUCY2C · congenital diarrhoea type 6 · DIAR6 · diarrhea 6 · diarrhea type 6 · diarrhoea 6 · diarrhoea type 6 · GUCY2C congenital diarrhea · GUCY2C congenital diarrhoea

Data availability: 27 ClinVar variants · 5 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 diarrhea 6

Related subtypes (11): congenital malabsorptive diarrhea 4, congenital diarrhea 7 with exudative enteropathy, congenital sodium diarrhea, diarrhea 12, with microvillus atrophy, diarrhea 9, diarrhea 10, protein-losing enteropathy type, diarrhea 11, malabsorptive, congenital, congenital secretory diarrhea, diarrhea 13, diarrhea 14, congenital, diarrhea 15, congenital

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

27 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 6 benign, 4 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30176	NM_004963.4(GUCY2C):c.2519G>T (p.Ser840Ile)	GUCY2C	Pathogenic	no assertion criteria provided
931137	NM_004963.4(GUCY2C):c.2324T>C (p.Leu775Pro)	GUCY2C	Pathogenic	criteria provided, single submitter
3075691	NM_004963.4(GUCY2C):c.2328A>C (p.Glu776Asp)	GUCY2C	Likely pathogenic	criteria provided, single submitter
3393482	NM_004963.4(GUCY2C):c.2323C>G (p.Leu775Val)	GUCY2C	Likely pathogenic	criteria provided, single submitter
3779714	NM_004963.4(GUCY2C):c.758del (p.Glu253fs)	GUCY2C	Likely pathogenic	criteria provided, single submitter
1429078	NM_004963.4(GUCY2C):c.1967A>G (p.Asn656Ser)	GUCY2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
870487	NM_004963.4(GUCY2C):c.1997A>G (p.Tyr666Cys)	GUCY2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
870488	NM_004963.4(GUCY2C):c.1540A>G (p.Ile514Val)	GUCY2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
985648	NM_004963.4(GUCY2C):c.2575A>G (p.Ile859Val)	GUCY2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031485	NM_004963.4(GUCY2C):c.2279A>G (p.Tyr760Cys)	GUCY2C	Uncertain significance	criteria provided, multiple submitters, no conflicts
1341819	NM_004963.4(GUCY2C):c.1562A>G (p.Asn521Ser)	GUCY2C	Uncertain significance	criteria provided, multiple submitters, no conflicts
1443889	NM_004963.4(GUCY2C):c.932C>T (p.Ser311Phe)	GUCY2C	Uncertain significance	criteria provided, multiple submitters, no conflicts
1485737	NM_004963.4(GUCY2C):c.143C>G (p.Ala48Gly)	GUCY2C	Uncertain significance	criteria provided, multiple submitters, no conflicts
1526101	NM_004963.4(GUCY2C):c.2356T>C (p.Tyr786His)	GUCY2C	Uncertain significance	criteria provided, single submitter
1696494	NM_004963.4(GUCY2C):c.2875+99A>G	GUCY2C	Uncertain significance	criteria provided, single submitter
2431538	NM_004963.4(GUCY2C):c.367T>A (p.Ser123Thr)	GUCY2C	Uncertain significance	criteria provided, single submitter
2827018	NM_004963.4(GUCY2C):c.629A>G (p.Glu210Gly)	GUCY2C	Uncertain significance	criteria provided, multiple submitters, no conflicts
2998309	NM_004963.4(GUCY2C):c.2783G>A (p.Cys928Tyr)	GUCY2C	Uncertain significance	criteria provided, multiple submitters, no conflicts
3248563	NM_004963.4(GUCY2C):c.1345G>C (p.Val449Leu)	GUCY2C	Uncertain significance	criteria provided, single submitter
977935	NM_004963.4(GUCY2C):c.1544T>C (p.Leu515Pro)	GUCY2C	Uncertain significance	no assertion criteria provided
1447315	NM_004963.4(GUCY2C):c.248T>C (p.Met83Thr)	GUCY2C-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1170460	NM_004963.4(GUCY2C):c.843T>G (p.Phe281Leu)	GUCY2C	Benign	criteria provided, multiple submitters, no conflicts
1267594	NM_004963.4(GUCY2C):c.1534-30C>G	GUCY2C	Benign	criteria provided, multiple submitters, no conflicts
402915	NM_004963.4(GUCY2C):c.2158-16dup	GUCY2C	Benign	criteria provided, multiple submitters, no conflicts
402916	NM_004963.4(GUCY2C):c.2022C>T (p.Ile674=)	GUCY2C	Benign	criteria provided, multiple submitters, no conflicts
402917	NM_004963.4(GUCY2C):c.612-11del	GUCY2C	Benign	criteria provided, multiple submitters, no conflicts
1165268	NM_004963.4(GUCY2C):c.612-16C>A	GUCY2C-AS1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · 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
GUCY2C	Definitive	Autosomal dominant	congenital diarrhea 6	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GUCY2C	Orphanet:103908	Congenital sodium diarrhea
GUCY2C	Orphanet:314373	Chronic infantile diarrhea due to guanylate cyclase 2C overactivity
GUCY2C	Orphanet:314376	Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency

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
GUCY2C	HGNC:4688	ENSG00000070019	P25092	Guanylyl cyclase C	gencc,clinvar
GUCY2C-AS1	HGNC:56054	ENSG00000214772		GUCY2C antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GUCY2C	Guanylyl cyclase C	Guanylyl cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GUCY2C	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom
GUCY2C-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
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
bone marrow cell	1
primordial germ cell in gonad	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GUCY2C	84	tissue_specific	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa
GUCY2C-AS1	117		yes	primordial germ cell in gonad, sural nerve, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GUCY2C	986
GUCY2C-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GUCY2C	P25092	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Intestinal infectious diseases	1	3806.7×	5e-04	GUCY2C
Digestion	1	571.0×	0.002	GUCY2C

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
cGMP biosynthetic process	1	1404.3×	0.002	GUCY2C
receptor guanylyl cyclase signaling pathway	1	1296.3×	0.002	GUCY2C
response to toxic substance	1	210.7×	0.008	GUCY2C
regulation of cell population proliferation	1	115.4×	0.011	GUCY2C
intracellular signal transduction	1	38.1×	0.026	GUCY2C

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GUCY2C	0	0
GUCY2C-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GUCY2C	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GUCY2C	4.6.1.2	guanylate cyclase

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GUCY2C
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GUCY2C-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GUCY2C	1	—
GUCY2C-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.