xanthinuria type II

Summary

xanthinuria type II (MONDO:0011346) is a disease caused by MOCOS (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: MOCOS (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 947

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	xanthinuria type II
Mondo ID	MONDO:0011346
MeSH	C566358
OMIM	603592
Orphanet	93602
DOID	DOID:0070453
UMLS	C1863688
MedGen	350953
GARD	0005620
Is cancer (heuristic)	no

Also known as: type 2 xanthinuria · type II xanthinuria · XAN2 · xanthine dehydrogenase and aldehyde oxidase combined deficiency of · xanthine dehydrogenase and aldehyde oxidase, combined deficiency of · xanthine dehydrogenase and xanthine aldehyde oxidase dual deficiency · xanthinuria type 2 · XDH and AOX dual deficiency

Data availability: 947 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › xanthinuria › hereditary xanthinuria › xanthinuria type II

Related subtypes (1): xanthinuria type I

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

600 retrieved; paginated sample, class counts are floors:

272 uncertain significance, 197 likely benign, 31 benign, 28 conflicting classifications of pathogenicity, 24 pathogenic, 23 benign/likely benign, 21 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1017655	NM_017947.4(MOCOS):c.1088_1089del (p.Leu363fs)	MOCOS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452243	NM_017947.4(MOCOS):c.916del (p.Ile306fs)	MOCOS	Pathogenic	criteria provided, single submitter
1452480	NM_017947.4(MOCOS):c.1665dup (p.Pro556fs)	MOCOS	Pathogenic	criteria provided, single submitter
1969820	NM_017947.4(MOCOS):c.1767_1768del (p.Tyr590fs)	MOCOS	Pathogenic	criteria provided, single submitter
2017024	NM_017947.4(MOCOS):c.2376G>A (p.Trp792Ter)	MOCOS	Pathogenic	criteria provided, single submitter
2085322	NM_017947.4(MOCOS):c.1809G>A (p.Trp603Ter)	MOCOS	Pathogenic	criteria provided, single submitter
253160	NM_017947.4(MOCOS):c.1255C>T (p.Arg419Ter)	MOCOS	Pathogenic	criteria provided, multiple submitters, no conflicts
253161	NM_017947.4(MOCOS):c.169G>C (p.Ala57Pro)	MOCOS	Pathogenic	no assertion criteria provided
253162	NM_017947.4(MOCOS):c.2326C>T (p.Arg776Cys)	MOCOS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253163	NM_017947.4(MOCOS):c.1037dup (p.Gln347fs)	MOCOS	Pathogenic	no assertion criteria provided
2835594	NM_017947.4(MOCOS):c.2268del (p.Ser757fs)	MOCOS	Pathogenic	criteria provided, single submitter
1075330	NM_000379.4(XDH):c.1343_1350del (p.Glu448fs)	XDH	Pathogenic	criteria provided, single submitter
1369362	NM_000379.4(XDH):c.2164A>T (p.Lys722Ter)	XDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1451493	NM_000379.4(XDH):c.598G>T (p.Glu200Ter)	XDH	Pathogenic	criteria provided, single submitter
1457782	NM_000379.4(XDH):c.641del (p.Pro214fs)	XDH	Pathogenic	criteria provided, multiple submitters, no conflicts
2015541	NM_000379.4(XDH):c.3711del (p.Ile1238fs)	XDH	Pathogenic	criteria provided, single submitter
2073968	NM_000379.4(XDH):c.1664dup (p.Ala556fs)	XDH	Pathogenic	criteria provided, single submitter
2415430	NM_000379.4(XDH):c.751C>T (p.Gln251Ter)	XDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2422980	NC_000002.11:g.(?31558824)(31637532_?)del	XDH	Pathogenic	criteria provided, single submitter
2422981	NC_000002.11:g.(?31588418)(31589011_?)del	XDH	Pathogenic	criteria provided, single submitter
2731116	NM_000379.4(XDH):c.2473C>T (p.Arg825Ter)	XDH	Pathogenic	criteria provided, multiple submitters, no conflicts
2743120	NM_000379.4(XDH):c.134del (p.Glu45fs)	XDH	Pathogenic	criteria provided, single submitter
2744635	NM_000379.4(XDH):c.575C>A (p.Ser192Ter)	XDH	Pathogenic	criteria provided, single submitter
2868102	NM_000379.4(XDH):c.547C>T (p.Gln183Ter)	XDH	Pathogenic	criteria provided, single submitter
2918237	NM_000379.4(XDH):c.2751dup (p.Pro918fs)	XDH	Pathogenic	criteria provided, single submitter
2954	NM_000379.4(XDH):c.682C>T (p.Arg228Ter)	XDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3247316	NC_000002.11:g.(?31621419)(31624214_?)del	XDH	Pathogenic	criteria provided, single submitter
335758	NM_000379.4(XDH):c.3847C>T (p.Arg1283Ter)	XDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1179050	NM_017947.4(MOCOS):c.2164+2T>C	MOCOS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179104	NM_017947.4(MOCOS):c.1335+1G>T	MOCOS	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 11 · 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
MOCOS	Strong	Autosomal recessive	xanthinuria type II	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MOCOS	Orphanet:93602	Xanthinuria type II
SORD	Orphanet:700508	Distal muscle weakness-foot deformity-elevated sorbitol level-hereditary motor neuropathy
SRD5A2	Orphanet:1331	Familial prostate cancer
SRD5A2	Orphanet:753	46,XY difference of sex development due to 5-alpha-reductase 2 deficiency
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
XDH	Orphanet:93601	Xanthinuria type I

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MOCOS	HGNC:18234	ENSG00000075643	Q96EN8	Molybdenum cofactor sulfurase	gencc,clinvar
SORD	HGNC:11184	ENSG00000140263	Q00796	Sorbitol dehydrogenase	clinvar
SRD5A2	HGNC:11285	ENSG00000277893	P31213	3-oxo-5-alpha-steroid 4-dehydrogenase 2	clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
XDH	HGNC:12805	ENSG00000158125	P47989	Xanthine dehydrogenase/oxidase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MOCOS	Molybdenum cofactor sulfurase	Sulfurates the molybdenum cofactor.
SORD	Sorbitol dehydrogenase	Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols.
SRD5A2	3-oxo-5-alpha-steroid 4-dehydrogenase 2	Converts testosterone (T) into 5-alpha-dihydrotestosterone (DHT) and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids.
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
XDH	Xanthine dehydrogenase/oxidase	Key enzyme in purine degradation.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Enzyme (other)	3	7.2×	0.010
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MOCOS	Other/Unknown	no		Aminotrans_V_dom, MoCF_Sase_C, MOCOS_middle
SORD	Enzyme (other)	yes	1.1.1.14	ADH_Zn_CS, GroES-like_sf, ADH-like_C
SRD5A2	Enzyme (other)	yes	1.3.1.22	3-oxo-5_a-steroid_4-DH_C, 3-oxo-5-alpha-steroid_4-DH, SRD5A/TECR
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
XDH	Enzyme (other)	yes	1.17.1.4	Ald_Oxase/Xan_DH_a/b, 2Fe-2S_ferredoxin-type, Mopterin_DH_FAD-bd

Expression context

Cohort genes with no expression data: 0.

5 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right lobe of liver	1
secondary oocyte	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
bronchial epithelial cell	1
corpus epididymis	1
epithelium of bronchus	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
ileal mucosa	1
jejunal mucosa	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MOCOS	193	ubiquitous	marker	secondary oocyte, right lobe of liver, liver
SORD	199	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
SRD5A2	66	tissue_specific	marker	corpus epididymis, bronchial epithelial cell, epithelium of bronchus
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
XDH	169	broad	marker	jejunal mucosa, ileal mucosa, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSC2	4,135
SORD	3,915
XDH	2,141
MOCOS	1,785
SRD5A2	1,103

Intra-cohort edges

A	B	Sources
MOCOS	XDH	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SORD	Q00796	3
TSC2	P49815	2
XDH	P47989	2
SRD5A2	P31213	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MOCOS	Q96EN8	80.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fructose biosynthesis	1	571.0×	0.015	SORD
Inhibition of TSC complex formation by AKT (PKB)	1	456.8×	0.015	TSC2
Formation of xylulose-5-phosphate	1	380.7×	0.015	SORD
Molybdenum cofactor biosynthesis	1	326.3×	0.015	MOCOS
Androgen biosynthesis	1	207.6×	0.015	SRD5A2
Purine catabolism	1	207.6×	0.015	XDH
Butyrophilin (BTN) family interactions	1	175.7×	0.015	XDH
AKT phosphorylates targets in the cytosol	1	163.1×	0.015	TSC2
Metabolism of steroid hormones	1	103.8×	0.020	SRD5A2
Azathioprine ADME	1	99.3×	0.020	XDH
Constitutive Signaling by AKT1 E17K in Cancer	1	84.6×	0.021	TSC2
Energy dependent regulation of mTOR by LKB1-AMPK	1	78.8×	0.021	TSC2
TBC/RABGAPs	1	51.9×	0.029	TSC2
Metabolism of water-soluble vitamins and cofactors	1	36.2×	0.039	MOCOS
Metabolism of steroids	1	27.5×	0.047	SRD5A2
TP53 Regulates Metabolic Genes	1	25.9×	0.047	TSC2
Metabolism of vitamins and cofactors	1	23.3×	0.047	MOCOS
Macroautophagy	1	23.1×	0.047	TSC2
Metabolism	2	4.7×	0.065	MOCOS, SRD5A2
Metabolism of lipids	1	6.3×	0.149	SRD5A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hypoxanthine catabolic process	1	3370.4×	0.003	XDH
xanthine catabolic process	1	3370.4×	0.003	XDH
phthalate metabolic process	1	3370.4×	0.003	SRD5A2
D-sorbitol catabolic process	1	1685.2×	0.003	SORD
guanine catabolic process	1	1685.2×	0.003	XDH
inosine catabolic process	1	1685.2×	0.003	XDH
deoxyinosine catabolic process	1	1685.2×	0.003	XDH
deoxyguanosine catabolic process	1	1685.2×	0.003	XDH
biphenyl metabolic process	1	1685.2×	0.003	SRD5A2
dibenzo-p-dioxin metabolic process	1	1685.2×	0.003	SRD5A2
molybdopterin cofactor metabolic process	1	1685.2×	0.003	MOCOS
xylitol catabolic process	1	1685.2×	0.003	SORD
xylitol metabolic process	1	1685.2×	0.003	SORD
deoxyadenosine catabolic process	1	1123.5×	0.004	XDH
molybdopterin cofactor biosynthetic process	1	1123.5×	0.004	MOCOS
GMP catabolic process	1	1123.5×	0.004	XDH
response to biphenyl	1	1123.5×	0.004	SRD5A2
adenosine catabolic process	1	842.6×	0.004	XDH
response to follicle-stimulating hormone	1	842.6×	0.004	SRD5A2
dAMP catabolic process	1	842.6×	0.004	XDH
fructose biosynthetic process	1	842.6×	0.004	SORD
IMP catabolic process	1	674.1×	0.005	XDH
obsolete D-glucuronate catabolic process to D-xylulose 5-phosphate	1	561.7×	0.005	SORD
dGMP catabolic process	1	561.7×	0.005	XDH
testosterone biosynthetic process	1	561.7×	0.005	SRD5A2
AMP catabolic process	1	481.5×	0.005	XDH
steroid catabolic process	1	481.5×	0.005	SRD5A2
Mo-molybdopterin cofactor biosynthetic process	1	481.5×	0.005	MOCOS
female genitalia development	1	481.5×	0.005	SRD5A2
obsolete amide catabolic process	1	421.3×	0.006	XDH

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
SORD	EPALRESTAT
SRD5A2	FINASTERIDE
XDH	FEBUXOSTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
XDH	16	4
SRD5A2	5	4
SORD	2	4
MOCOS	0	0
TSC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EPALRESTAT	4	SORD
FINASTERIDE	4	SRD5A2
FEBUXOSTAT	4	XDH
ALLOPURINOL	4	XDH
INDOMETHACIN	4	XDH
THIOGUANINE	4	XDH
QUERCETIN	3	SORD, XDH
GAMOLENIC ACID	3	SRD5A2
RUTIN	3	XDH
ADENINE	3	XDH
EPRISTERIDE	2	SRD5A2
TUROSTERIDE	2	SRD5A2
BEXLOSTERIDE	2	SRD5A2
TOPIROXOSTAT	2	XDH
LUTEOLIN	2	XDH
ISOQUERCETIN	2	XDH
FISETIN	2	XDH
BROPIRIMINE	2	XDH
GENISTEIN	2	XDH
BAICALEIN	2	XDH
OXYPURINOL	2	XDH
KAEMPFEROL	1	XDH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
XDH	184	Binding:184
SRD5A2	119	Binding:115, Functional:4
SORD	17	Binding:16, Functional:1
TSC2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SORD	1.1.1.14	L-iditol 2-dehydrogenase
SRD5A2	1.3.1.22, 1.3.99.5	3-oxo-5alpha-steroid 4-dehydrogenase (NADP+), 3-oxo-5alpha-steroid 4-dehydrogenase (acceptor)
XDH	1.17.1.4, 1.17.3.2	xanthine dehydrogenase, xanthine oxidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SRD5A2	119
XDH	184

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

22 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)
EPALRESTAT	4	SORD
FINASTERIDE	4	SRD5A2
FEBUXOSTAT	4	XDH
ALLOPURINOL	4	XDH
INDOMETHACIN	4	XDH
THIOGUANINE	4	XDH
QUERCETIN	3	SORD, XDH
GAMOLENIC ACID	3	SRD5A2
RUTIN	3	XDH
ADENINE	3	XDH
EPRISTERIDE	2	SRD5A2
TUROSTERIDE	2	SRD5A2
BEXLOSTERIDE	2	SRD5A2
TOPIROXOSTAT	2	XDH
LUTEOLIN	2	XDH
ISOQUERCETIN	2	XDH
FISETIN	2	XDH
BROPIRIMINE	2	XDH
GENISTEIN	2	XDH
BAICALEIN	2	XDH
OXYPURINOL	2	XDH
KAEMPFEROL	1	XDH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SORD, SRD5A2, XDH
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	2	MOCOS, TSC2

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)
MOCOS	0	XDH
TSC2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.