Lymphopenia

Summary

Lymphopenia (MONDO:0003783) is a disease with 23 cohort genes (9 GWAS associations across 2 studies) and 23 clinical trials. Top therapeutic interventions include niacinamide, interleukin-7, and efineptakin alfa.

At a glance

• Cohort genes: 23
• GWAS associations: 9
• ClinVar variants: 19
• Clinical trials: 23

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lymphopenia
Mondo ID	MONDO:0003783
MeSH	D008231
DOID	DOID:614
ICD-10-CM	D72.810
ICD-11	298296736
SNOMED CT	48813009
UMLS	C0024312
MedGen	7418
Is cancer (heuristic)	no

Also known as: lymphocytopenia · lymphopenia · lymphopenia (disease)

Data availability: 19 ClinVar variants · 9 GWAS associations (2 studies) · 1 HPO phenotype.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › immune system disorder › leukocyte disorder › leukopenia › lymphopenia

Related subtypes (1): agranulocytosis

Subtypes (1): idiopathic CD4-positive T-lymphocytopenia

Genetics & variants

GWAS landscape

9 GWAS associations across 2 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs12249496	1e-06	LINC01163 - LINC02667	?	2.2
rs17417060	1e-06	TMEM72-AS1, TMEM72	?	2.1
kgp3442760	1e-06		?	1.9
kgp1734375	2e-06		?	3.4
kgp5383559	3e-06		?	2
kgp4348860	4e-06		?	2.4
kgp4224365	5e-06		?	2.9
kgp2538268	6e-06		?	1.8
kgp6724547	6e-06		?	3.8

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST009545	Sangurdekar D	2019	206	1,052	Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate.
GCST009546	Sangurdekar D	2019	42	1,052	Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	1
Tier 4: intronic/intergenic	8

MAF distribution

Bucket	Variants
common (>=0.05)	2
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	7

Functional consequences

Consequence	Count
unknown	7
regulatory_region_variant	1
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs12249496	10	128875540	G>T	0.05	regulatory_region_variant	LINC01163 - LINC02667	1e-06	Tier 3: regulatory
rs17417060	10	44917329	A>G	0.05	intron_variant	TMEM72-AS1, TMEM72	1e-06	Tier 4: intronic/intergenic
kgp3442760							1e-06	Tier 4: intronic/intergenic
kgp1734375							2e-06	Tier 4: intronic/intergenic
kgp5383559							3e-06	Tier 4: intronic/intergenic
kgp4348860							4e-06	Tier 4: intronic/intergenic
kgp4224365							5e-06	Tier 4: intronic/intergenic
kgp2538268							6e-06	Tier 4: intronic/intergenic
kgp6724547							6e-06	Tier 4: intronic/intergenic

ClinVar germline variants

19 retrieved; paginated sample, class counts are floors:

12 likely benign, 3 uncertain significance, 3 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1679869	NM_001161403.3(LIMS2):c.802+1G>A	LIMS2	Uncertain significance	no assertion criteria provided
1679868	NM_007183.4(PKP3):c.118C>T (p.Arg40Trp)	PKP3	Uncertain significance	no assertion criteria provided
1679870	NM_006537.4(USP3):c.941T>G (p.Phe314Cys)	USP3	Uncertain significance	no assertion criteria provided
718379	NM_001183.6(ATP6AP1):c.539G>A (p.Arg180His)	ATP6AP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1679864	NM_001109659.2(C16orf92):c.128G>A (p.Arg43Lys)	C16orf92	Likely benign	no assertion criteria provided
703138	NM_152274.5(CCNQ):c.338G>A (p.Arg113His)	CCNQ	Likely benign	criteria provided, multiple submitters, no conflicts
1679858	NM_001710.6(CFB):c.1942A>T (p.Lys648Ter)	CFB	Likely benign	no assertion criteria provided
1679866	NM_004284.6(CHD1L):c.1954G>A (p.Ala652Thr)	CHD1L	Likely benign	no assertion criteria provided
1679867	NM_001136018.4(EPHX1):c.1004C>T (p.Thr335Met)	EPHX1	Benign	no assertion criteria provided
1043778	NM_004523.4(KIF11):c.3053A>G (p.His1018Arg)	KIF11	Likely benign	criteria provided, multiple submitters, no conflicts
726756	NM_004523.4(KIF11):c.77+5G>C	KIF11	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1679865	NM_005462.5(MAGEC1):c.2T>C (p.Met1Thr)	LOC126863334	Likely benign	criteria provided, single submitter
1679859	NM_001401501.2(MUC16):c.27739T>C (p.Ser9247Pro)	MUC16	Likely benign	criteria provided, single submitter
932519	NM_006468.8(POLR3C):c.251G>A (p.Arg84Gln)	POLR3C	Likely benign	criteria provided, multiple submitters, no conflicts
252613	NM_003052.5(SLC34A1):c.284G>A (p.Arg95His)	SLC34A1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1679860	NM_003260.5(TLE2):c.2114G>A (p.Ser705Asn)	TLE2	Likely benign	criteria provided, single submitter
1679861	NM_003260.5(TLE2):c.946G>A (p.Gly316Arg)	TLE2	Likely benign	criteria provided, single submitter
1679862	NM_015117.3(ZC3H3):c.1646C>T (p.Ser549Leu)	ZC3H3	Likely benign	criteria provided, single submitter
1679863	NM_015117.3(ZC3H3):c.1203G>C (p.Lys401Asn)	ZC3H3	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CFB	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
SLC34A1	Orphanet:157215	Hereditary hypophosphatemic rickets with hypercalciuria
SLC34A1	Orphanet:244305	Dominant hypophosphatemia with nephrolithiasis or osteoporosis
SLC34A1	Orphanet:300547	Autosomal recessive infantile hypercalcemia
SLC34A1	Orphanet:3337	Primary Fanconi renotubular syndrome
RIN2	Orphanet:217335	RIN2 syndrome
CCNQ	Orphanet:140952	Syndactyly-telecanthus-anogenital and renal malformations syndrome
EPHX1	Orphanet:238475	Familial hypercholanemia
KIF11	Orphanet:2526	Microcephaly-lymphedema-chorioretinopathy syndrome
MN1	Orphanet:263662	Familial multiple meningioma
MN1	Orphanet:693549	Facial dysmorphism-Intellectual disability-rhombencephalosynapsis syndrome
ATP6AP1	Orphanet:692790	ATP6AP1-CDG

Cohort genes → proteins

23 cohort genes, 21 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	8
multi_evidence	15

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CFB	HGNC:1037	ENSG00000243649	P00751	Complement factor B	clinvar
SLC34A1	HGNC:11019	ENSG00000131183	Q06495	Sodium-dependent phosphate transport protein 2A	clinvar
TLE2	HGNC:11838	ENSG00000065717	Q04725	Transducin-like enhancer protein 2	clinvar
USP3	HGNC:12626	ENSG00000140455	Q9Y6I4	Ubiquitin carboxyl-terminal hydrolase 3	clinvar
MUC16	HGNC:15582	ENSG00000181143	Q8WXI7	Mucin-16	clinvar
LIMS2	HGNC:16084	ENSG00000072163	Q7Z4I7	LIM and senescent cell antigen-like-containing domain protein 2	clinvar
RIN2	HGNC:18750	ENSG00000132669	Q8WYP3	Ras and Rab interactor 2	gwas
CHD1L	HGNC:1916	ENSG00000131778	Q86WJ1	ATP-dependent chromatin remodeler CHD1L	clinvar
RASL11B	HGNC:23804	ENSG00000128045	Q9BPW5	Ras-like protein family member 11B	gwas
FIMP1	HGNC:26346	ENSG00000167194	Q96LL3	Fertilization-influencing membrane protein	clinvar
LINC01618	HGNC:27195	ENSG00000250302		long intergenic non-protein coding RNA 1618	gwas
TMEM72-AS1	HGNC:27349	ENSG00000224812		TMEM72 antisense RNA 1	gwas
CCNQ	HGNC:28434	ENSG00000262919	Q8N1B3	Cyclin-Q	clinvar
ZC3H3	HGNC:28972	ENSG00000014164	Q8IXZ2	Zinc finger CCCH domain-containing protein 3	clinvar
POLR3C	HGNC:30076	ENSG00000186141	Q9BUI4	DNA-directed RNA polymerase III subunit RPC3	clinvar
SCFD2	HGNC:30676	ENSG00000184178	Q8WU76	Sec1 family domain-containing protein 2	gwas
TMEM72	HGNC:31658	ENSG00000187783	A0PK05	Transmembrane protein 72	gwas
EPHX1	HGNC:3401	ENSG00000143819	P07099	Epoxide hydrolase 1	clinvar
ERVMER34-1	HGNC:42970	ENSG00000226887	Q9H9K5	Endogenous retroviral envelope protein HEMO	gwas
KIF11	HGNC:6388	ENSG00000138160	P52732	Kinesin-like protein KIF11	clinvar
MN1	HGNC:7180	ENSG00000169184	Q10571	Transcriptional activator MN1	gwas
ATP6AP1	HGNC:868	ENSG00000071553	Q15904	V-type proton ATPase subunit S1	clinvar
PKP3	HGNC:9025	ENSG00000184363	Q9Y446	Plakophilin-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CFB	Complement factor B	Precursor of the catalytic component of the C3 and C5 convertase complexes of the alternative pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the…
SLC34A1	Sodium-dependent phosphate transport protein 2A	Involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane.
TLE2	Transducin-like enhancer protein 2	Transcriptional corepressor that binds to a number of transcription factors.
USP3	Ubiquitin carboxyl-terminal hydrolase 3	Deubiquitinase that plays a role in several cellular processes including transcriptional regulation, cell cycle progression or innate immunity.
MUC16	Mucin-16	Thought to provide a protective, lubricating barrier against particles and infectious agents at mucosal surfaces.
LIMS2	LIM and senescent cell antigen-like-containing domain protein 2	Adapter protein in a cytoplasmic complex linking beta-integrins to the actin cytoskeleton, bridges the complex to cell surface receptor tyrosine kinases and growth factor receptors.
RIN2	Ras and Rab interactor 2	Ras effector protein.
CHD1L	ATP-dependent chromatin remodeler CHD1L	ATP-dependent chromatin remodeler that mediates chromatin-remodeling following DNA damage.
FIMP1	Fertilization-influencing membrane protein	May play a role in sperm-oocyte fusion during fertilization.
CCNQ	Cyclin-Q	Activating cyclin for the cyclin-associated kinase CDK10.
ZC3H3	Zinc finger CCCH domain-containing protein 3	Required for the export of polyadenylated mRNAs from the nucleus.
POLR3C	DNA-directed RNA polymerase III subunit RPC3	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
SCFD2	Sec1 family domain-containing protein 2	May be involved in protein transport.
EPHX1	Epoxide hydrolase 1	Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water.
ERVMER34-1	Endogenous retroviral envelope protein HEMO	Endogenous envelope proteins originate from retroviral envelope proteins, which mediate receptor recognition and membrane fusion during early infection.
KIF11	Kinesin-like protein KIF11	Motor protein required for establishing a bipolar spindle and thus contributing to chromosome congression during mitosis.
MN1	Transcriptional activator MN1	Transcriptional activator which specifically regulates expression of TBX22 in the posterior region of the developing palate.
ATP6AP1	V-type proton ATPase subunit S1	Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles.
PKP3	Plakophilin-3	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

Protein-family classification

Druggable: 4 · Difficult: 4 · Unknown: 15 · Druggable fraction: 0.17

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
Protease	2	3.2×	0.611
Other/Unknown	15	1.2×	0.611
Scaffold/PPI	2	1.5×	0.646
Enzyme (other)	2	1.0×	0.728
Transcription factor	2	0.7×	0.786

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CFB	Protease	yes	3.4.21.47	Sushi_SCR_CCP_dom, Trypsin_dom, Peptidase_S1A
SLC34A1	Other/Unknown	no		Na/Pi_transpt
TLE2	Scaffold/PPI	no		WD40_rpt, Groucho/TLE_N, Groucho_enhance
USP3	Protease	yes		Peptidase_C19_UCH, Znf_UBP, Znf_RING/FYVE/PHD
MUC16	Other/Unknown	no		SEA_dom, MUC16, SEA_dom_sf
LIMS2	Transcription factor	no		Znf_LIM, PINCH-1-4-like, LIMS1/2-like_LIM1
RIN2	Scaffold/PPI	no		RA_dom, SH2, VPS9
CHD1L	Other/Unknown	no		SNF2_N, Helicase_C-like, DNA/RNA_helicase_DEAH_CS
RASL11B	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
FIMP1	Other/Unknown	no		FIMP
LINC01618	Other/Unknown	no
TMEM72-AS1	Other/Unknown	no
CCNQ	Other/Unknown	no		Cyclin_N, Cyclin-like_dom, Cyclin-like_sf
ZC3H3	Transcription factor	no		Znf_CCCH, Znf_CCCH_sf
POLR3C	Other/Unknown	no		RNA_pol_III_Rpc82_C, RNA_pol_III_RPC82-rel_HTH, WH-like_DNA-bd_sf
SCFD2	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
TMEM72	Other/Unknown	no		TMEM72
EPHX1	Enzyme (other)	yes	3.3.2.9	AB_hydrolase_1, Epox_hydrolase-like, Epoxide_hydrolase
ERVMER34-1	Other/Unknown	no		TLV/ENV_coat_polyprotein
KIF11	Enzyme (other)	yes	5.6.1.3	Kinesin_motor_dom, Kinesin_motor_CS, Kinesin-assoc_MT-bd_dom
MN1	Other/Unknown	no		MN1
ATP6AP1	Other/Unknown	no		Ac45_acc_su, VAS1_LD, VAS1/VOA1_TM
PKP3	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold

Expression context

Cohort genes with no expression data: 0.

19 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)	23
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	4
ganglionic eminence	3
right lobe of liver	2
adult mammalian kidney	2
cerebellar hemisphere	2
nasal cavity epithelium	2
tendon of biceps brachii	2
primordial germ cell in gonad	2
metanephros cortex	2
placenta	2
ventricular zone	2
gall bladder	1
liver	1
kidney epithelium	1
nephron tubule	1
cerebellar cortex	1
right hemisphere of cerebellum	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CFB	134	broad	marker	right lobe of liver, liver, gall bladder
SLC34A1	52	tissue_specific	marker	nephron tubule, adult mammalian kidney, kidney epithelium
TLE2	293	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
USP3	284	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
MUC16	113	broad	marker	nasal cavity epithelium, epithelium of bronchus, bronchus
LIMS2	237	ubiquitous	marker	apex of heart, lower esophagus muscularis layer, lower esophagus
RIN2	296	ubiquitous	marker	choroid plexus epithelium, tendon of biceps brachii, hair follicle
CHD1L	233	ubiquitous	marker	primordial germ cell in gonad, C1 segment of cervical spinal cord, cerebellar hemisphere
RASL11B	155	broad	marker	right ovary, left ovary, metanephros cortex
FIMP1	114		yes	right testis, left testis, male germ line stem cell (sensu Vertebrata) in testis
LINC01618	119		marker	male germ line stem cell (sensu Vertebrata) in testis, placenta, ventricular zone
TMEM72-AS1	154	broad	yes	buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence
CCNQ	255	ubiquitous	marker	tendon of biceps brachii, left ventricle myocardium, myocardium
ZC3H3	184	ubiquitous	marker	right lobe of liver, oocyte, secondary oocyte
POLR3C	260	ubiquitous	marker	primordial germ cell in gonad, calcaneal tendon, stromal cell of endometrium
SCFD2	251	ubiquitous	yes	pancreatic ductal cell, ileal mucosa, tibialis anterior
TMEM72	108	tissue_specific	marker	renal medulla, adult mammalian kidney, nasal cavity epithelium
EPHX1	276	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, adrenal cortex
ERVMER34-1	140	broad	yes	placenta, male germ line stem cell (sensu Vertebrata) in testis, metanephros cortex
KIF11	205	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
MN1	252	ubiquitous	marker	ganglionic eminence, vastus lateralis, skeletal muscle tissue of biceps brachii
ATP6AP1	291	ubiquitous	marker	endometrium epithelium, Brodmann (1909) area 10, paraflocculus
PKP3	206	broad	marker	lower esophagus mucosa, skin of abdomen, skin of leg

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF11	3,788
SLC34A1	3,362
CHD1L	3,332
POLR3C	2,985
EPHX1	2,678
CFB	1,997
RASL11B	1,941
ATP6AP1	1,759
PKP3	1,595
MUC16	1,584

Intra-cohort edges

A	B	Sources
KIF11	MN1	biogrid_interaction

Structural data

PDB: 7 · AlphaFold-only: 14 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF11	P52732	62
POLR3C	Q9BUI4	32
CFB	P00751	26
ATP6AP1	Q15904	9
CHD1L	Q86WJ1	7
MUC16	Q8WXI7	4
LIMS2	Q7Z4I7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EPHX1	P07099	95.06
SCFD2	Q8WU76	92.33
CCNQ	Q8N1B3	88.81
RASL11B	Q9BPW5	79.69
USP3	Q9Y6I4	79.40
SLC34A1	Q06495	72.24
PKP3	Q9Y446	69.24
TLE2	Q04725	68.40
FIMP1	Q96LL3	65.84
RIN2	Q8WYP3	64.30
TMEM72	A0PK05	57.48
ZC3H3	Q8IXZ2	52.45
ERVMER34-1	Q9H9K5	44.55
MN1	Q10571	42.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 61. Enrichment computed across 23 evidence-associated genes (14 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 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC34A1 causes hypophosphatemic nephrolithiasis/osteoporosis 1 (NPHLOP1)	1	407.9×	0.119	SLC34A1
Type II Na+/Pi cotransporters	1	203.9×	0.119	SLC34A1
Alternative complement activation	1	163.1×	0.119	CFB
Activation of C3 and C5	1	90.6×	0.119	CFB
Repression of WNT target genes	1	51.0×	0.119	TLE2
Defective GALNT3 causes HFTC	1	51.0×	0.119	MUC16
Defective GALNT12 causes CRCS1	1	51.0×	0.119	MUC16
Cell-extracellular matrix interactions	1	48.0×	0.119	LIMS2
Defective C1GALT1C1 causes TNPS	1	48.0×	0.119	MUC16
RNA Polymerase III Chain Elongation	1	45.3×	0.119	POLR3C
RNA Polymerase III Transcription Termination	1	35.5×	0.119	POLR3C
Termination of O-glycan biosynthesis	1	35.5×	0.119	MUC16
Dectin-2 family	1	30.2×	0.119	MUC16
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	30.2×	0.119	POLR3C
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	29.1×	0.119	POLR3C
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	29.1×	0.119	POLR3C
Insulin receptor recycling	1	27.2×	0.119	ATP6AP1
Surfactant metabolism	1	26.3×	0.119	SLC34A1
Transferrin endocytosis and recycling	1	26.3×	0.119	ATP6AP1
RNA Polymerase III Transcription Initiation	1	24.0×	0.119	POLR3C
RNA Polymerase III Transcription	1	23.3×	0.119	POLR3C
Nuclear RNA decay	1	22.1×	0.119	ZC3H3
Cytosolic sensors of pathogen-associated DNA	1	20.4×	0.119	POLR3C
RNA Polymerase III Abortive And Retractive Initiation	1	19.9×	0.119	POLR3C
Dual Incision in GG-NER	1	18.5×	0.119	CHD1L
Formation of Incision Complex in GG-NER	1	18.1×	0.119	CHD1L
NOTCH1 Intracellular Domain Regulates Transcription	1	17.0×	0.119	TLE2
C-type lectin receptors (CLRs)	1	17.0×	0.119	MUC16
Deactivation of the beta-catenin transactivating complex	1	16.6×	0.119	TLE2
Regulation of Complement cascade	1	16.6×	0.119	CFB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hydrocarbon catabolic process	1	887.0×	0.031	EPHX1
negative regulation of cholangiocyte proliferation	1	887.0×	0.031	LIMS2
indole metabolic process	1	443.5×	0.031	SLC34A1
gentamycin metabolic process	1	443.5×	0.031	SLC34A1
arsenate ion transmembrane transport	1	443.5×	0.031	SLC34A1
cholangiocyte proliferation	1	443.5×	0.031	LIMS2
positive regulation of phosphate transmembrane transport	1	443.5×	0.031	SLC34A1
spindle elongation	1	295.6×	0.031	KIF11
epoxide metabolic process	1	295.6×	0.031	EPHX1
negative regulation of mRNA catabolic process	1	295.6×	0.031	PKP3
negative regulation of hepatocyte proliferation	1	295.6×	0.031	LIMS2
regulation of cytokine production involved in immune response	1	221.7×	0.031	PKP3
cellular response to phosphate starvation	1	221.7×	0.031	SLC34A1
regulation of hair follicle development	1	221.7×	0.031	PKP3
cellular response to metal ion	1	221.7×	0.031	SLC34A1
positive regulation of sodium-dependent phosphate transport	1	221.7×	0.031	SLC34A1
obsolete regulation of cellular pH	1	177.4×	0.031	ATP6AP1
regulation of mitotic centrosome separation	1	177.4×	0.031	KIF11
cellular response to staurosporine	1	177.4×	0.031	SLC34A1
endosome to plasma membrane protein transport	1	177.4×	0.031	ATP6AP1
intramembranous ossification	1	147.8×	0.031	MN1
mitotic centrosome separation	1	147.8×	0.031	KIF11
positive regulation of activin receptor signaling pathway	1	147.8×	0.031	ZC3H3
positive regulation of membrane potential	1	147.8×	0.031	SLC34A1
positive regulation of vitamin D receptor signaling pathway	1	147.8×	0.031	MN1
tricarboxylic acid metabolic process	1	147.8×	0.031	SLC34A1
desmosome assembly	1	126.7×	0.031	PKP3
response to mercury ion	1	126.7×	0.031	SLC34A1
regulation of cell cycle G2/M phase transition	1	126.7×	0.031	CCNQ
desmosome organization	1	110.9×	0.031	PKP3

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Filgrastim, Plerixafor.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 19

Druggability breadth: 8 of 23 evidence-associated genes (35%) 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
CFB	IPTACOPAN
SLC34A1	SODIUM PHOSPHATE, DIBASIC, ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KIF11	6	3
SLC34A1	2	4
EPHX1	2	2
CFB	1	4
TLE2	0	0
USP3	0	0
MUC16	0	0
LIMS2	0	0
RIN2	0	0
CHD1L	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IPTACOPAN	4	CFB
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	SLC34A1
POTASSIUM PHOSPHATE, MONOBASIC	4	SLC34A1
GOSSYPOL	3	KIF11
TRICLOCARBAN	2	EPHX1
AR9281	2	EPHX1
AZD-4877	2	KIF11
LITRONESIB	2	KIF11
ISPINESIB	2	KIF11
FILANESIB	2	KIF11
SB-743921	1	KIF11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
KIF11	193	Binding:185, Functional:8
CFB	33	Binding:33
EPHX1	30	Binding:18, ADMET:12
SLC34A1	8	Binding:7, Functional:1
ATP6AP1	7	Binding:7
CHD1L	4	Binding:4
USP3	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFB	3.4.21.47	alternative-complement-pathway C3/C5 convertase
EPHX1	3.3.2.9	microsomal epoxide hydrolase
KIF11	5.6.1.3	plus-end-directed kinesin ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KIF11	193

Pharmacogenomics

Cohort genes with a PharmGKB record: 21; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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)
IPTACOPAN	4	CFB
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	SLC34A1
POTASSIUM PHOSPHATE, MONOBASIC	4	SLC34A1
GOSSYPOL	3	KIF11
TRICLOCARBAN	2	EPHX1
AR9281	2	EPHX1
AZD-4877	2	KIF11
LITRONESIB	2	KIF11
ISPINESIB	2	KIF11
FILANESIB	2	KIF11
SB-743921	1	KIF11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CFB, SLC34A1
B	Phased (≥1) drug, not yet approved	2	EPHX1, KIF11
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	USP3
E	Difficult family or no structure, no drug	18	TLE2, MUC16, LIMS2, RIN2, CHD1L, RASL11B, FIMP1, LINC01618, TMEM72-AS1, CCNQ (+8 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TLE2	0	—
USP3	3	—
MUC16	0	—
LIMS2	0	—
RIN2	0	—
CHD1L	4	—
RASL11B	0	—
FIMP1	0	—
LINC01618	0	—
TMEM72-AS1	0	—
CCNQ	0	—
ZC3H3	0	—
POLR3C	0	—
SCFD2	0	—
TMEM72	0	—
ERVMER34-1	0	—
MN1	0	—
ATP6AP1	7	—
PKP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 23.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	11
Not specified	9
PHASE1	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07492875	PHASE3	WITHDRAWN	Study of Nogapendekin Alfa Inbakicept and iNKT Cells in Critically Ill Adults With Severe Community-Acquired Pneumonia
NCT06584006	PHASE2	RECRUITING	Thymalfasin and Recombinant Human IL-2 Injections in Treating Lymphocytopenia for Patients With Malignant Hematological Tumors
NCT07258160	PHASE2	RECRUITING	Evaluation of the Effect of Cordycepin on CD8+ Lymphocytopenia in Patients With Solid Tumors
NCT07267234	PHASE2	NOT_YET_RECRUITING	PRaG-1 Plus PRaG Therapy in Advanced Solid Tumors: A Prospective Clinical Trial (PRaG 10.0)
NCT07578558	PHASE2	NOT_YET_RECRUITING	NAI for Sepsis With Persistent Lymphopenia
NCT00771810	PHASE2	COMPLETED	Study of Drug to Reduce Thrombocytopenia in Patients Receiving Chemo for Ovarian, Fallopian Tube or Peritoneal Cancer
NCT04379076	PHASE2	TERMINATED	InterLeukin-7 (CYT107) to Improve Clinical Outcomes in Lymphopenic pAtients With COVID-19 Infection UK Cohort
NCT04407689	PHASE2	TERMINATED	InterLeukin-7 to Improve Clinical Outcomes in Lymphopenic pAtients With COVID-19 Infection FR BL Cohort
NCT04426201	PHASE2	TERMINATED	InterLeukin-7 to Improve Clinical Outcomes in Lymphopenic Patients With COVID-19 Infection ( ILIAD-7-US-O )
NCT04442178	PHASE2	TERMINATED	InterLeukin-7 to Improve Clinical Outcomes in Lymphopenic pAtients With COVID-19 Infection ( ILIAD-7-US-I )
NCT04927169	PHASE2	TERMINATED	InterLeukin-7 to Improve Clinical Outcomes in Lymphopenic pAtients With COVID-19 Infection (Brazil Cohort)
NCT07492888	PHASE2	WITHDRAWN	Nogapendekin Alfa-Inbakicept and iNKT Cells for Critically Ill Adults With Severe Community-Acquired Pneumonia (With or Without Sepsis/ARDS)
NCT00477321	PHASE1	COMPLETED	Safety Study of IL-7 in HIV-infected Patients (Inspire)
NCT02659800	PHASE1	TERMINATED	Study of the Effect NT-I7 on CD4 Counts in Patients With High Grade Gliomas
NCT06181656	Not specified	RECRUITING	Serologic Response to Pneumococcal Vaccination Among Esophageal Cancer Patients With High Grade Lymphopenia After Chemoradiation
NCT06956547	Not specified	AVAILABLE	Expanded Access Use of Nogapendekin-alfa Inbakicept in the Reversal and Maintenance of Absolute Lymphocyte Count (ALC) for the Treatment of Lymphopenia Induced by Chemotherapy, Immunotherapy, and/or Radiation Therapy
NCT01660347	Not specified	WITHDRAWN	Donor Stem Cell Boost in Treating Patients With Low Blood Cells After Donor Stem Cell Transplant
NCT02698683	Not specified	COMPLETED	Lymphocyte Count as a Sign of Immunoparalysis and Its Correlation With Nutritional Status in Septic Pediatric Patients
NCT04404608	Not specified	COMPLETED	Etiology of Lymphopenia in Covid19 Infection
NCT04800731	Not specified	COMPLETED	Study of Lymphopenia as a Specific Biomarker or Prognostic Risk Factor for Disease Severity in Elderly Patients With COVID-19
NCT04910230	Not specified	COMPLETED	Nicotinamide-based Supportive Therapy in Lymphopenia for Patients With COVID-19
NCT05889169	Not specified	COMPLETED	Stroke-induced Immunodepression in Neurorehabilitation
NCT06368349	Not specified	COMPLETED	Persistent Lymphopenia in Liver Transplantation and Its Molecular Insights for Hepatocellular Carcinoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NIACINAMIDE	4	1
INTERLEUKIN-7	2	6
EFINEPTAKIN ALFA	2	1
INBAKICEPT	2	1
TALFIRASTIDE	2	1