Congenital portosystemic shunt

disease

On this page

Also known as congenital portosystemic venous fistula

Summary

Congenital portosystemic shunt (MONDO:0018811) is a disease with 38 cohort genes and 2 clinical trials.

At a glance

Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
Cohort genes: 38
ClinVar variants: 51
Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	3	Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital portosystemic shunt
Mondo ID	MONDO:0018811
Orphanet	480531
ICD-11	682625970
UMLS	C1290495
MedGen	712860
GARD	0021979
Is cancer (heuristic)	no

Also known as: congenital portosystemic venous fistula

Data availability: 51 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › congenital portosystemic shunt

Subtypes (1): patent ductus venosus

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

51 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 21 conflicting classifications of pathogenicity, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
360568	NM_000048.4(ASL):c.1124A>G (p.Tyr375Cys)	ASL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
728678	NM_001286577.2(C2CD3):c.131C>A (p.Thr44Asn)	C2CD3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16959	NM_000394.4(CRYAA):c.145C>T (p.Arg49Cys)	CRYAA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2763499	NM_001277115.2(DNAH11):c.11647C>T (p.Leu3883Phe)	DNAH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359599	NM_001277115.2(DNAH11):c.794G>A (p.Arg265His)	DNAH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
408166	NM_000135.4(FANCA):c.2546del (p.Ser849fs)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265477	NM_002016.2(FLG):c.7264G>T (p.Glu2422Ter)	FLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1048245	NM_000512.5(GALNS):c.1480A>G (p.Met494Val)	GALNS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4288	NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)	GBA1	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
4654	NM_006118.4(HAX1):c.256C>T (p.Arg86Ter)	HAX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4825	NM_000441.2(SLC26A4):c.2168A>G (p.His723Arg)	LOC123956210	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
700041	NM_080860.4(RSPH1):c.94G>A (p.Gly32Arg)	LOC126653391	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45771	NM_016239.4(MYO15A):c.8767C>T (p.Arg2923Ter)	MYO15A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13405	NM_000311.5(PRNP):c.538G>A (p.Val180Ile)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13340	NM_002834.5(PTPN11):c.236A>G (p.Gln79Arg)	PTPN11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
143164	NM_178857.6(RP1L1):c.1972C>T (p.Arg658Ter)	RP1L1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
779819	NM_001036.6(RYR3):c.2747A>C (p.Lys916Thr)	RYR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1131764	NM_014159.7(SETD2):c.7261A>G (p.Thr2421Ala)	SETD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
448391	NM_001126108.2(SLC12A3):c.1195C>T (p.Arg399Cys)	SLC12A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5999	NM_014252.4(SLC25A15):c.815C>T (p.Thr272Ile)	SLC25A15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191850	NM_001267550.2(TTN):c.94016C>T (p.Thr31339Ile)	TTN-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
753846	NM_003334.4(UBA1):c.1243G>A (p.Gly415Arg)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4644003	NM_032827.7(ATOH8):c.119A>G (p.Tyr40Cys)	ATOH8	Uncertain significance	criteria provided, multiple submitters, no conflicts
4813091	NM_032827.7(ATOH8):c.320C>T (p.Ala107Val)	ATOH8	Uncertain significance	criteria provided, single submitter
1806580	NM_001286577.2(C2CD3):c.112C>T (p.Arg38Cys)	C2CD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4813088	NM_005140.3(CNGA2):c.1378G>A (p.Ala460Thr)	CNGA2	Uncertain significance	criteria provided, single submitter
4813103	NM_001291540.2(CT45A9):c.403C>T (p.Arg135Ter)	CT45A9	Uncertain significance	criteria provided, single submitter
4813089	NM_000106.6(CYP2D6):c.989G>A (p.Arg330His)	CYP2D6	Uncertain significance	criteria provided, single submitter
4813097	NM_015512.5(DNAH1):c.6451T>A (p.Phe2151Ile)	DNAH1	Uncertain significance	criteria provided, single submitter
4813098	NM_015512.5(DNAH1):c.12566A>G (p.Lys4189Arg)	DNAH1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 74 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC12A3	Orphanet:358	Gitelman syndrome
SLC25A15	Orphanet:415	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
UBA1	Orphanet:1145	Infantile-onset X-linked spinal muscular atrophy
UBA1	Orphanet:596753	VEXAS syndrome
RP1L1	Orphanet:247834	Occult macular dystrophy
RP1L1	Orphanet:791	Retinitis pigmentosa
PGRMC1	Orphanet:98994	Total early-onset cataract
HAX1	Orphanet:99749	Kostmann syndrome
SETD2	Orphanet:597738	Luscan-Lumish syndrome
SETD2	Orphanet:597743	SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome
CNGA2	Orphanet:88620	Isolated congenital anosmia
CRYAA	Orphanet:1377	Cataract-microcornea syndrome
CRYAA	Orphanet:441452	Early-onset lamellar cataract
CRYAA	Orphanet:98988	Early-onset anterior polar cataract
CRYAA	Orphanet:98991	Early-onset nuclear cataract
CRYAA	Orphanet:98994	Total early-onset cataract
C2CD3	Orphanet:434179	Orofaciodigital syndrome type 14
DNAH1	Orphanet:244	Primary ciliary dyskinesia
DNAH1	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
DNAH11	Orphanet:244	Primary ciliary dyskinesia
FANCA	Orphanet:84	Fanconi anemia
FGFR1	Orphanet:168953	Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1	Orphanet:2117	Hartsfield syndrome
FGFR1	Orphanet:220386	Semilobar holoprosencephaly
FGFR1	Orphanet:2396	Encephalocraniocutaneous lipomatosis
FGFR1	Orphanet:251576	Gliosarcoma
FGFR1	Orphanet:251579	Giant cell glioblastoma
FGFR1	Orphanet:251615	Pilomyxoid astrocytoma
FGFR1	Orphanet:2645	Osteoglosphonic dysplasia
FGFR1	Orphanet:280200	Microform holoprosencephaly
FGFR1	Orphanet:314950	Primary hypereosinophilic syndrome
FGFR1	Orphanet:3157	Septo-optic dysplasia spectrum
FGFR1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FGFR1	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGFR1	Orphanet:478	Kallmann syndrome
FGFR1	Orphanet:93258	Pfeiffer syndrome type 1
FGFR1	Orphanet:93924	Lobar holoprosencephaly

Cohort genes → proteins

38 cohort genes, 37 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	38

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR3	HGNC:10485	ENSG00000198838	Q15413	Ryanodine receptor 3	clinvar
SLC12A3	HGNC:10912	ENSG00000070915	P55017	Solute carrier family 12 member 3	clinvar
SLC25A15	HGNC:10985	ENSG00000102743	Q9Y619	Mitochondrial ornithine transporter 1	clinvar
TAF7L	HGNC:11548	ENSG00000102387	Q5H9L4	Transcription initiation factor TFIID subunit 7-like	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
UBA1	HGNC:12469	ENSG00000130985	P22314	Ubiquitin-like modifier-activating enzyme 1	clinvar
SYTL4	HGNC:15588	ENSG00000102362	Q96C24	Synaptotagmin-like protein 4	clinvar
RP1L1	HGNC:15946	ENSG00000183638	Q8IWN7	Retinitis pigmentosa 1-like 1 protein	clinvar
PGRMC1	HGNC:16090	ENSG00000101856	O00264	Membrane-associated progesterone receptor component 1	clinvar
HAX1	HGNC:16915	ENSG00000143575	O00165	HCLS1-associated protein X-1	clinvar
GPR173	HGNC:18186	ENSG00000184194	Q9NS66	Probable G-protein coupled receptor 173	clinvar
SETD2	HGNC:18420	ENSG00000181555	Q9BYW2	Histone-lysine N-methyltransferase SETD2	clinvar
NHERF4	HGNC:19891	ENSG00000172367	Q86UT5	Na(+)/H(+) exchange regulatory cofactor NHE-RF4	clinvar
CNGA2	HGNC:2149	ENSG00000183862	Q16280	Cyclic nucleotide-gated channel alpha-2	clinvar
CRYAA	HGNC:2388	ENSG00000160202	P02489	Alpha-crystallin A chain	clinvar
ATOH8	HGNC:24126	ENSG00000168874	Q96SQ7	Transcription factor ATOH8	clinvar
C2CD3	HGNC:24564	ENSG00000168014	Q4AC94	C2 domain-containing protein 3	clinvar
JMJD4	HGNC:25724	ENSG00000081692	Q9H9V9	2-oxoglutarate and iron-dependent oxygenase JMJD4	clinvar
CYP2D6	HGNC:2625	ENSG00000100197	P10635	Cytochrome P450 2D6	clinvar
FER1L6	HGNC:28065	ENSG00000214814	Q2WGJ9	Fer-1-like protein 6	clinvar
SFI1	HGNC:29064	ENSG00000198089	A8K8P3	Protein SFI1 homolog	clinvar
ENTREP2	HGNC:29075	ENSG00000104059	O60320	Protein ENTREP2	clinvar
DNAH1	HGNC:2940	ENSG00000114841	Q9P2D7	Dynein axonemal heavy chain 1	clinvar
DNAH11	HGNC:2942	ENSG00000105877	Q96DT5	Dynein axonemal heavy chain 11	clinvar
EEA1	HGNC:3185	ENSG00000102189	Q15075	Early endosome antigen 1	clinvar
FANCA	HGNC:3582	ENSG00000187741	O15360	Fanconi anemia group A protein	clinvar
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar
FLG	HGNC:3748	ENSG00000143631	P20930	Filaggrin	clinvar
GALNS	HGNC:4122	ENSG00000141012	P34059	N-acetylgalactosamine-6-sulfatase	clinvar
GBA1	HGNC:4177	ENSG00000177628	P04062	Lysosomal acid glucosylceramidase	clinvar
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar
CT45A9	HGNC:51262	ENSG00000270946	P0DMV2	Cancer/testis antigen family 45 member A9	clinvar
ASL	HGNC:746	ENSG00000126522	P04424	Argininosuccinate lyase	clinvar
MYO15A	HGNC:7594	ENSG00000091536	Q9UKN7	Unconventional myosin-XV	clinvar
MYO9A	HGNC:7608	ENSG00000066933	B2RTY4	Unconventional myosin-IXa	clinvar
PLOD3	HGNC:9083	ENSG00000106397	O60568	Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3	clinvar
PRNP	HGNC:9449	ENSG00000171867	F7VJQ1	Alternative prion protein	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RYR3	Ryanodine receptor 3	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm in muscle and thereby plays a role in triggering muscle contraction.
SLC12A3	Solute carrier family 12 member 3	Electroneutral sodium and chloride ion cotransporter, which acts as a key mediator of sodium and chloride reabsorption in kidney distal convoluted tubules.
SLC25A15	Mitochondrial ornithine transporter 1	Mitochondrial ornithine-citrulline antiporter.
TAF7L	Transcription initiation factor TFIID subunit 7-like	Probably functions as a spermatogenesis-specific component of the DNA-binding general transcription factor complex TFIID, a multimeric protein complex that plays a central role in mediating promoter responses to various activators and repr…
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
UBA1	Ubiquitin-like modifier-activating enzyme 1	Catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin-proteasome system.
SYTL4	Synaptotagmin-like protein 4	Modulates exocytosis of dense-core granules and secretion of hormones in the pancreas and the pituitary.
RP1L1	Retinitis pigmentosa 1-like 1 protein	Required for the differentiation of photoreceptor cells.
PGRMC1	Membrane-associated progesterone receptor component 1	Component of a progesterone-binding protein complex.
HAX1	HCLS1-associated protein X-1	Recruits the Arp2/3 complex to the cell cortex and regulates reorganization of the cortical actin cytoskeleton via its interaction with KCNC3 and the Arp2/3 complex.
GPR173	Probable G-protein coupled receptor 173	Is a receptor for the SMIM20 derived peptides Phoenixin-14 and Phoenixin-20.
SETD2	Histone-lysine N-methyltransferase SETD2	Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate.
NHERF4	Na(+)/H(+) exchange regulatory cofactor NHE-RF4	Acts as a regulatory protein that associates with GUCY2C and negatively modulates its heat-stable enterotoxin-mediated activation.
CNGA2	Cyclic nucleotide-gated channel alpha-2	Pore-forming subunit of the olfactory cyclic nucleotide-gated channel.
CRYAA	Alpha-crystallin A chain	Contributes to the transparency and refractive index of the lens.
ATOH8	Transcription factor ATOH8	Transcription factor that binds a palindromic (canonical) core consensus DNA sequence 5’-CANNTG- 3’ known as an E-box element, possibly as a heterodimer with other bHLH proteins.
C2CD3	C2 domain-containing protein 3	Component of the centrioles that acts as a positive regulator of centriole elongation.
JMJD4	2-oxoglutarate and iron-dependent oxygenase JMJD4	Catalyzes the 2-oxoglutarate and iron-dependent C4-lysyl hydroxylation of ETF1 at ‘Lys-63’ thereby promoting the translational termination efficiency of ETF1.
CYP2D6	Cytochrome P450 2D6	A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids.
FER1L6	Fer-1-like protein 6	Calcium/phospholipid-binding protein which is essential for proper development of skeletal and cardiac muscle.
SFI1	Protein SFI1 homolog	Plays a role in the dynamic structure of centrosome-associated contractile fibers via its interaction with CETN2.
DNAH1	Dynein axonemal heavy chain 1	Force generating protein of cilia required for sperm flagellum motility.
DNAH11	Dynein axonemal heavy chain 11	Force generating protein required for cilia beating in respiratory epithelia.
EEA1	Early endosome antigen 1	Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate and participates in endosomal trafficking.
FANCA	Fanconi anemia group A protein	DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function.
FGFR1	Fibroblast growth factor receptor 1	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.
FLG	Filaggrin	Aggregates keratin intermediate filaments and promotes disulfide-bond formation among the intermediate filaments during terminal differentiation of mammalian epidermis.
GBA1	Lysosomal acid glucosylceramidase	Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose.
ASL	Argininosuccinate lyase	Catalyzes the reversible cleavage of L-argininosuccinate to fumarate and L-arginine, an intermediate step reaction in the urea cycle mostly providing for hepatic nitrogen detoxification into excretable urea as well as de novo L-arginine sy…
MYO15A	Unconventional myosin-XV	Myosins are actin-based motor molecules with ATPase activity.
MYO9A	Unconventional myosin-IXa	Myosins are actin-based motor molecules with ATPase activity.
PLOD3	Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3	Multifunctional enzyme that catalyzes a series of essential post-translational modifications on Lys residues in procollagen.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 12 · Difficult: 6 · Unknown: 20 · Druggable fraction: 0.32

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
Ion channel	2	5.9×	0.301
Phosphatase	2	4.4×	0.301
Enzyme (other)	5	1.6×	0.552
Kinase	2	1.5×	0.641
Scaffold/PPI	3	1.4×	0.641
Other/Unknown	20	0.9×	0.855
Transcription factor	3	0.7×	0.855
GPCR	1	0.6×	0.855

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR3	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
SLC12A3	Other/Unknown	no		SLC12A3, AA-permease/SLC12A_dom, SLC12A_fam
SLC25A15	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, Mitochondrial_Carrier
TAF7L	Other/Unknown	no		TAFII55_prot_cons_reg, TAF7
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
UBA1	Enzyme (other)	yes	2.3.2.23	UBQ/SUMO-activ_enz_E1-like, ThiF_NAD_FAD-bd, UBQ-activ_enz_E1_CS
SYTL4	Transcription factor	no		C2_dom, Synaptotagmin, Rab_BD
RP1L1	Other/Unknown	no		Doublecortin_dom, Doublecortin_dom_sf
PGRMC1	Other/Unknown	no		Cyt_B5-like_heme/steroid-bd, Cyt_B5-like_heme/steroid_sf, MAPR/NEUFC/NENF-like
HAX1	Other/Unknown	no		HAX-1
GPR173	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM, GPCR_Orphan/Phoenixin
SETD2	Scaffold/PPI	no	2.1.1.359	WW_dom, SET_dom, Post-SET_dom
NHERF4	Scaffold/PPI	no		PDZ, PDZ_sf, NHER
CNGA2	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
CRYAA	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N
ATOH8	Transcription factor	no		bHLH_dom, ATOH8_bHLH, HLH_DNA-bd_sf
C2CD3	Other/Unknown	no		C2_dom, C2_domain_sf, C2_C2CD3
JMJD4	Other/Unknown	no		JmjC_dom, JMJD6_ArgDemeth/LysHydrox
CYP2D6	Enzyme (other)	yes	1.14.14.1	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_E_grp-I_CYP2D-like
FER1L6	Other/Unknown	no		C2_dom, Ferlin_B-domain, FerIin_dom
SFI1	Other/Unknown	no		CACF_protein
ENTREP2	Other/Unknown	no		CD20-like_TM, ENTREP1-3
DNAH1	Other/Unknown	no		Dhc_D6_P-loop, Dhc_linker, Dhc_D4
DNAH11	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
EEA1	Transcription factor	no		Znf_FYVE, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
FANCA	Other/Unknown	no		FANCA, Fanconi_A_N, Fanconi_A_C
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FLG	Other/Unknown	no		S100/CaBP7/8-like_CS, EF_hand_dom, Filaggrin
GALNS	Phosphatase	yes	3.1.6.12	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
GBA1	Enzyme (other)	yes	3.2.1.45	Glyco_hydro_30, GH_hydrolase_sf, GH30_C
TTN-AS1	Other/Unknown	no
CT45A9	Other/Unknown	no		INT_SG_DDX_CT_C, Integrator_subunit6
ASL	Enzyme (other)	yes	4.3.2.1	Fumarate_lyase_fam, L-Aspartase-like, Argininosuccinate_lyase
MYO15A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, FERM_domain, MyTH4_dom
MYO9A	Other/Unknown	no		IQ_motif_EF-hand-BS, RA_dom, RhoGAP_dom
PLOD3	Enzyme (other)	yes	1.14.11.4	Procol_lys_dOase, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph
PRNP	Other/Unknown	no		Prion, Prion_copper_b_octapeptide, Prion/Doppel_prot_b-ribbon_dom
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	37
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	4
right lobe of liver	4
primordial germ cell in gonad	4
right uterine tube	4
duodenum	3
left testis	3
bronchial epithelial cell	3
calcaneal tendon	3
stromal cell of endometrium	3
right hemisphere of cerebellum	2
sural nerve	2
adult mammalian kidney	2
right testis	2
biceps brachii	2
buccal mucosa cell	2
hindlimb stylopod muscle	2
adenohypophysis	2
cortical plate	2
colonic epithelium	2
mucosa of transverse colon	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RYR3	233	broad	marker	diaphragm, sural nerve, right hemisphere of cerebellum
SLC12A3	85	tissue_specific	marker	adult mammalian kidney, nephron tubule, kidney
SLC25A15	198	ubiquitous	marker	liver, right lobe of liver, duodenum
TAF7L	136	tissue_specific	marker	right testis, left testis, primordial germ cell in gonad
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
UBA1	292	ubiquitous	marker	endometrium epithelium, renal medulla, pharyngeal mucosa
SYTL4	230	ubiquitous	marker	left ovary, right ovary, body of uterus
RP1L1	30	tissue_specific	yes	primordial germ cell in gonad, buccal mucosa cell, bone marrow cell
PGRMC1	301	ubiquitous	marker	seminal vesicle, caput epididymis, adrenal tissue
HAX1	295	ubiquitous	marker	apex of heart, heart right ventricle, hindlimb stylopod muscle
GPR173	169	ubiquitous	yes	cortical plate, ganglionic eminence, adenohypophysis
SETD2	291	ubiquitous	marker	tendon of biceps brachii, endothelial cell, colonic epithelium
NHERF4	129	tissue_specific	marker	mucosa of transverse colon, duodenum, rectum
CNGA2	2		yes	colonic epithelium, ventricular zone, cortical plate
CRYAA	42		marker	adult mammalian kidney, right lobe of liver, liver
ATOH8	228	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, right lung
C2CD3	282	ubiquitous	marker	sural nerve, right uterine tube, bronchial epithelial cell
JMJD4	178	ubiquitous	marker	left adrenal gland cortex, left adrenal gland, right adrenal gland
CYP2D6	131	tissue_specific	yes	right lobe of liver, liver, duodenum
FER1L6	65		marker	rectum, olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis
SFI1	241	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
ENTREP2	124	tissue_specific	marker	primordial germ cell in gonad, Ammon’s horn, primary visual cortex
DNAH1	183	tissue_specific	marker	right uterine tube, bronchial epithelial cell, bronchus
DNAH11	163	broad	marker	right uterine tube, bronchial epithelial cell, bronchus
EEA1	277	ubiquitous	marker	calcaneal tendon, upper leg skin, biceps brachii
FANCA	185	ubiquitous	marker	right testis, ventricular zone, left testis
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon
FLG	162	tissue_specific	yes	upper leg skin, upper arm skin, skin of hip
GALNS	258	ubiquitous	marker	right uterine tube, sperm, male germ cell
GBA1	134	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, placenta

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPN11	6,009
FGFR1	5,693
UBA1	4,870
SETD2	4,668
TTN	4,237
EEA1	3,995
FANCA	3,036
PRNP	2,594
GBA1	2,568
PGRMC1	2,476

Intra-cohort edges

A	B	Sources
ASL	SLC25A15	string_interaction
HAX1	PRNP	biogrid_interaction

Structural data

PDB: 24 · AlphaFold-only: 13 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN11	Q06124	115
FGFR1	P11362	83
PRNP	F7VJQ1	70
TTN	Q8WZ42	64
GBA1	P04062	58
SETD2	Q9BYW2	43
PLOD3	O60568	18
CYP2D6	P10635	14
SLC12A3	P55017	12
RYR3	Q15413	10
UBA1	P22314	9
FANCA	O15360	6
CRYAA	P02489	5
EEA1	Q15075	4
SYTL4	Q96C24	3
CNGA2	Q16280	2
DNAH1	Q9P2D7	2
GALNS	P34059	2
ASL	P04424	2
PGRMC1	O00264	1
NHERF4	Q86UT5	1
SFI1	A8K8P3	1
FLG	P20930	1
MYO15A	Q9UKN7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
JMJD4	Q9H9V9	94.04
SLC25A15	Q9Y619	87.43
GPR173	Q9NS66	81.94
FER1L6	Q2WGJ9	76.78
CT45A9	P0DMV2	68.99
TAF7L	Q5H9L4	68.14
ATOH8	Q96SQ7	65.44
HAX1	O00165	60.06
ENTREP2	O60320	59.09
MYO9A	B2RTY4	58.07
C2CD3	Q4AC94	55.65
RP1L1	Q8IWN7	38.97
DNAH11	Q96DT5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 168. Enrichment computed across 38 evidence-associated genes (27 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 27 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MPS IV - Morquio syndrome A	1	423.0×	0.058	GALNS
Defective SLC12A3 causes Gitelman syndrome (GS)	1	423.0×	0.058	SLC12A3
ASL variants cause argininosuccinate aciduria	1	423.0×	0.058	ASL
Urea cycle	2	65.1×	0.058	SLC25A15, ASL
PI-3K cascade:FGFR1	2	38.5×	0.058	FGFR1, PTPN11
FRS-mediated FGFR1 signaling	2	33.8×	0.058	FGFR1, PTPN11
Negative regulation of FGFR1 signaling	2	27.3×	0.058	FGFR1, PTPN11
Signaling by FGFR1 amplification mutants	1	211.5×	0.079	FGFR1
SLC25A15 variants cause hyperornithinemia-hyperammonemia-homocitrullinemia syndrome	1	211.5×	0.079	SLC25A15
PI3K Cascade	2	20.1×	0.079	FGFR1, PTPN11
Intestinal infectious diseases	1	141.0×	0.108	NHERF4
FGFR1c and Klotho ligand binding and activation	1	105.7×	0.122	FGFR1
Signaling by plasma membrane FGFR1 fusions	1	105.7×	0.122	FGFR1
MET activates PTPN11	1	84.6×	0.132	PTPN11
Co-inhibition by BTLA	1	84.6×	0.132	PTPN11
Biosynthesis of maresin-like SPMs	1	70.5×	0.137	CYP2D6
Cation-coupled Chloride cotransporters	1	60.4×	0.137	SLC12A3
STAT5 Activation	1	60.4×	0.137	PTPN11
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	52.9×	0.137	FGFR1
FGFR1b ligand binding and activation	1	47.0×	0.137	FGFR1
Netrin mediated repulsion signals	1	47.0×	0.137	PTPN11
MAPK1 (ERK2) activation	1	42.3×	0.137	PTPN11
STAT5 activation downstream of FLT3 ITD mutants	1	42.3×	0.137	PTPN11
MAPK3 (ERK1) activation	1	38.5×	0.137	PTPN11
Signaling by Leptin	1	38.5×	0.137	PTPN11
Interleukin-6 signaling	1	35.2×	0.137	PTPN11
Signaling by activated point mutants of FGFR1	1	35.2×	0.137	FGFR1
Miscellaneous substrates	1	35.2×	0.137	CYP2D6
CYP2E1 reactions	1	35.2×	0.137	CYP2D6
Activated NTRK2 signals through FRS2 and FRS3	1	35.2×	0.137	PTPN11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 34 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ammonia assimilation cycle	1	495.6×	0.050	ASL
isoquinoline alkaloid metabolic process	1	495.6×	0.050	CYP2D6
negative regulation of cortisol secretion	1	495.6×	0.050	PTPN11
negative regulation of growth hormone secretion	1	495.6×	0.050	PTPN11
negative regulation of organofluorine metabolic process	1	495.6×	0.050	CYP2D6
protein O-linked glycosylation via galactose	1	495.6×	0.050	PLOD3
positive regulation of neuronal action potential	1	495.6×	0.050	GBA1
negative regulation of synapse organization	1	495.6×	0.050	PGRMC1
formation of primary germ layer	1	247.8×	0.050	ATOH8
alkaloid metabolic process	1	247.8×	0.050	CYP2D6
cerebellar Purkinje cell layer formation	1	247.8×	0.050	GBA1
neural plate axis specification	1	247.8×	0.050	C2CD3
microvillus organization	1	247.8×	0.050	PTPN11
determination of left/right asymmetry in nervous system	1	247.8×	0.050	DNAH11
obsolete L-arginine biosynthetic process via ornithine	1	247.8×	0.050	ASL
intestinal epithelial cell migration	1	247.8×	0.050	PTPN11
vitamin D3 metabolic process	1	247.8×	0.050	FGFR1
modification of synaptic structure	1	247.8×	0.050	PGRMC1
beta-glucoside catabolic process	1	247.8×	0.050	GBA1
positive regulation of mitotic cell cycle DNA replication	1	247.8×	0.050	FGFR1
regulation of germ cell proliferation	1	247.8×	0.050	FANCA
positive regulation of parathyroid hormone secretion	1	247.8×	0.050	FGFR1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	247.8×	0.050	FGFR1
L-arginine biosynthetic process	1	165.2×	0.050	ASL
glucosylceramide catabolic process	1	165.2×	0.050	GBA1
alkaloid catabolic process	1	165.2×	0.050	CYP2D6
regulation of phosphate transport	1	165.2×	0.050	FGFR1
synaptic vesicle to endosome fusion	1	165.2×	0.050	EEA1
cerebellar cortex formation	1	165.2×	0.050	PTPN11
termination of signal transduction	1	165.2×	0.050	GBA1

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 32

Druggability breadth: 18 of 38 evidence-associated genes (47%) 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
PGRMC1	ENCORAFENIB
CYP2D6	LEVOSALBUTAMOL
FGFR1	PONATINIB
GBA1	MIGALASTAT
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP2D6	436	4
FGFR1	93	4
GBA1	12	4
PTPN11	8	4
SETD2	3	2
PGRMC1	1	4
RYR3	0	0
SLC12A3	0	0
SLC25A15	0	0
TAF7L	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENCORAFENIB	4	PGRMC1
LEVOSALBUTAMOL	4	CYP2D6
DIENESTROL	4	CYP2D6
CLOTRIMAZOLE	4	CYP2D6
COLCHICINE	4	CYP2D6
DIBUCAINE	4	CYP2D6
PHENELZINE	4	CYP2D6
FELBAMATE	4	CYP2D6
BRETYLIUM TOSYLATE	4	CYP2D6
IMIPRAMINE	4	CYP2D6
BENZNIDAZOLE	4	CYP2D6
DROPERIDOL	4	CYP2D6
AMOXAPINE	4	CYP2D6
DICYCLOMINE	4	CYP2D6
DULOXETINE	4	CYP2D6
CELECOXIB	4	CYP2D6
PROPANTHELINE	4	CYP2D6
PROPOXYCAINE	4	CYP2D6
PROPARACAINE	4	CYP2D6
BENOXINATE	4	CYP2D6
NICARDIPINE HYDROCHLORIDE	4	CYP2D6
BUPIVACAINE HYDROCHLORIDE	4	CYP2D6
DIMENHYDRINATE	4	CYP2D6
TETRAHYDROZOLINE HYDROCHLORIDE	4	CYP2D6
GUANABENZ ACETATE	4	CYP2D6
PHENTOLAMINE MESYLATE	4	CYP2D6
HALOFANTRINE HYDROCHLORIDE	4	CYP2D6
BENZTHIAZIDE	4	CYP2D6
LOXAPINE SUCCINATE	4	CYP2D6
LEVOBUPIVACAINE	4	CYP2D6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
CYP2D6	3,659	ADMET:3565, Binding:91, Functional:2, Toxicity:1
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13
PTPN11	588	Binding:585, Functional:2, ADMET:1
GBA1	436	Binding:403, Functional:33
SETD2	64	Binding:64
UBA1	38	Binding:38
CRYAA	25	Binding:25
GALNS	15	Binding:15
PGRMC1	4	Binding:4
HAX1	3	Binding:3
RYR3	2	Binding:2
GPR173	2	Binding:2
SLC12A3	1	Functional:1
TTN	1	Binding:1
EEA1	1	Binding:1
MYO15A	1	Binding:1
PLOD3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
UBA1	2.3.2.23, 6.2.1.45, 6.2.1.64	E2 ubiquitin-conjugating enzyme, E1 ubiquitin-activating enzyme, E1 NEDD8-activating enzyme
SETD2	2.1.1.359	[histone H3]-lysine36 N-trimethyltransferase
CYP2D6	1.14.14.1, 1.14.99.38	unspecific monooxygenase, cholesterol 25-monooxygenase
FGFR1	2.7.10.1	receptor protein-tyrosine kinase
GALNS	3.1.6.12, 3.1.6.4	N-acetylgalactosamine-4-sulfatase, N-acetylgalactosamine-6-sulfatase
GBA1	3.2.1.45	glucosylceramidase
ASL	4.3.2.1	argininosuccinate lyase
PLOD3	1.14.11.4, 2.4.1.50, 2.4.1.66	procollagen-lysine 5-dioxygenase, procollagen galactosyltransferase, procollagen glucosyltransferase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CYP2D6	3,659
FGFR1	1,465
GBA1	436
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 37; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CYP2D6	1

Chemical tractability of cohort targets

30 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)
ENCORAFENIB	4	PGRMC1
LEVOSALBUTAMOL	4	CYP2D6
DIENESTROL	4	CYP2D6
CLOTRIMAZOLE	4	CYP2D6
COLCHICINE	4	CYP2D6
DIBUCAINE	4	CYP2D6
PHENELZINE	4	CYP2D6
FELBAMATE	4	CYP2D6
BRETYLIUM TOSYLATE	4	CYP2D6
IMIPRAMINE	4	CYP2D6
BENZNIDAZOLE	4	CYP2D6
DROPERIDOL	4	CYP2D6
AMOXAPINE	4	CYP2D6
DICYCLOMINE	4	CYP2D6
DULOXETINE	4	CYP2D6
CELECOXIB	4	CYP2D6
PROPANTHELINE	4	CYP2D6
PROPOXYCAINE	4	CYP2D6
PROPARACAINE	4	CYP2D6
BENOXINATE	4	CYP2D6
NICARDIPINE HYDROCHLORIDE	4	CYP2D6
BUPIVACAINE HYDROCHLORIDE	4	CYP2D6
DIMENHYDRINATE	4	CYP2D6
TETRAHYDROZOLINE HYDROCHLORIDE	4	CYP2D6
GUANABENZ ACETATE	4	CYP2D6
PHENTOLAMINE MESYLATE	4	CYP2D6
HALOFANTRINE HYDROCHLORIDE	4	CYP2D6
BENZTHIAZIDE	4	CYP2D6
LOXAPINE SUCCINATE	4	CYP2D6
LEVOBUPIVACAINE	4	CYP2D6

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	PGRMC1, CYP2D6, FGFR1, GBA1, PTPN11
B	Phased (≥1) drug, not yet approved	1	SETD2
C	Druggable family + PDB, no drug	7	RYR3, TTN, UBA1, CNGA2, GALNS, ASL, PLOD3
D	Druggable family + AlphaFold only, no drug	1	GPR173
E	Difficult family or no structure, no drug	24	SLC12A3, SLC25A15, TAF7L, SYTL4, RP1L1, HAX1, NHERF4, CRYAA, ATOH8, C2CD3 (+14 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR3	2	—
SLC12A3	1	—
SLC25A15	0	—
TAF7L	0	—
TTN	1	—
UBA1	38	—
SYTL4	0	—
RP1L1	0	—
HAX1	3	—
GPR173	2	—
NHERF4	0	—
CNGA2	0	—
CRYAA	25	—
ATOH8	0	—
C2CD3	0	—
JMJD4	0	—
FER1L6	0	—
SFI1	0	—
ENTREP2	0	—
DNAH1	0	—
DNAH11	0	—
EEA1	1	—
FANCA	0	—
FLG	0	—
GALNS	15	—
TTN-AS1	0	—
CT45A9	0	—
ASL	0	—
MYO15A	1	—
MYO9A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06041906	Not specified	ENROLLING_BY_INVITATION	International Registry of Congenital Portosystemic Shunt (IRCPSS)
NCT07314814	Not specified	NOT_YET_RECRUITING	Genetic Hallmarks of Patients With Congenital Portosystemic Shunts and Portopulmonary Hypertension

Cohort genes: RYR3, SLC12A3, SLC25A15, TAF7L, TTN, UBA1, SYTL4, RP1L1, PGRMC1, HAX1, GPR173, SETD2, NHERF4, CNGA2, CRYAA, ATOH8, C2CD3, JMJD4, CYP2D6, FER1L6, SFI1, ENTREP2, DNAH1, DNAH11, EEA1, FANCA, FGFR1, FLG, GALNS, GBA1, TTN-AS1, CT45A9, ASL, MYO15A, MYO9A, PLOD3, PRNP, PTPN11