AL amyloidosis

Summary

AL amyloidosis (MONDO:0019438) is a disease with 18 cohort genes (19 GWAS associations across 10 studies) and 109 clinical trials. The dominant Reactome pathway is MITF-M-dependent gene expression (3 cohort genes). Top therapeutic interventions include dexamethasone, teclistamab, and foscarnet.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 18
• GWAS associations: 19
• Phenotypes (HPO): 55
• Clinical trials: 109

Clinical features

Epidemiology

Prevalence records

81 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1.044	Worldwide	Validated
Point prevalence	1-9 / 100 000	5.127	Worldwide	Validated
Annual incidence	1-9 / 100 000	1.1177	Europe	Validated
Point prevalence	1-9 / 100 000	5.5311	Europe	Validated
Annual incidence	1-9 / 100 000	1.166	Austria	Validated
Annual incidence	1-9 / 100 000	1.122	Belgium	Validated
Annual incidence	1-9 / 100 000	1.174	Bulgaria	Validated
Annual incidence	1-9 / 100 000	1.156	Croatia	Validated
Annual incidence	1-9 / 1 000 000	0.894	Cyprus	Validated
Annual incidence	1-9 / 100 000	1.109	Czech Republic	Validated
Annual incidence	1-9 / 100 000	1.124	Denmark	Validated
Annual incidence	1-9 / 100 000	1.107	Estonia	Validated
Annual incidence	1-9 / 100 000	1.187	Finland	Validated
Annual incidence	1-9 / 100 000	1.152	France	Validated
Annual incidence	1-9 / 100 000	1.294	Germany	Validated
Annual incidence	1-9 / 100 000	1.254	Greece	Validated
Annual incidence	1-9 / 100 000	1.088	Hungary	Validated
Annual incidence	1-9 / 1 000 000	0.948	Iceland	Validated
Annual incidence	1-9 / 1 000 000	0.913	Ireland	Validated
Annual incidence	1-9 / 100 000	1.329	Italy	Validated

Signs & symptoms

Clinical features (HPO)

55 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0000077	Abnormality of the kidney	Frequent (30-79%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000100	Nephrotic syndrome	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:0003115	Abnormal EKG	Frequent (30-79%)
HP:0006530	Abnormal pulmonary interstitial morphology	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0010702	Increased circulating antibody level	Frequent (30-79%)
HP:0012280	Hepatic amyloidosis	Frequent (30-79%)
HP:0012592	Albuminuria	Frequent (30-79%)
HP:0025077	Decreased QRS voltage	Frequent (30-79%)
HP:0025552	Periorbital purpura	Frequent (30-79%)
HP:0031185	Increased circulating NT-proBNP concentration	Frequent (30-79%)
HP:0031326	Monoclonal light chain cardiac amyloidosis	Frequent (30-79%)
HP:0032613	Renal interstitial amyloid deposits	Frequent (30-79%)
HP:0100639	Erectile dysfunction	Frequent (30-79%)
HP:0410173	Increased circulating troponin I concentration	Frequent (30-79%)
HP:0410174	Increased troponin T level in blood	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000217	Xerostomia	Occasional (5-29%)
HP:0000978	Bruising susceptibility	Occasional (5-29%)
HP:0001713	Abnormal cardiac ventricle morphology	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002870	Obstructive sleep apnea	Occasional (5-29%)
HP:0003073	Hypoalbuminemia	Occasional (5-29%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Occasional (5-29%)
HP:0003270	Abdominal distention	Occasional (5-29%)
HP:0005120	Abnormal cardiac atrium morphology	Occasional (5-29%)
HP:0005307	Postural hypotension with compensatory tachycardia	Occasional (5-29%)
HP:0008321	Reduced factor X activity	Occasional (5-29%)
HP:0008652	Autonomic erectile dysfunction	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0010286	Abnormal salivary gland morphology	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0012185	Constrictive median neuropathy	Occasional (5-29%)
HP:0012332	Abnormal autonomic nervous system physiology	Occasional (5-29%)
HP:0012398	Peripheral edema	Occasional (5-29%)
HP:0025389	Pulmonary interstitial high-resolution computed tomography abnormality	Occasional (5-29%)
HP:0030164	Jaw claudication	Occasional (5-29%)
HP:0031246	Nonproductive cough	Occasional (5-29%)
HP:0031595	Abnormal P wave	Occasional (5-29%)
HP:0032550	Howell-Jolly bodies	Occasional (5-29%)
HP:0012664	Reduced left ventricular ejection fraction	Excluded (0%)
HP:0000158	Macroglossia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	AL amyloidosis
Mondo ID	MONDO:0019438
MeSH	C531616
Orphanet	85443
DOID	DOID:0080933
ICD-11	1061366491, 113043090
NCIT	C158963
UMLS	C0268381
MedGen	75674
GARD	0005797
MedDRA	10036673
Is cancer (heuristic)	no

Also known as: amyloidosis AL · amyloidosis primary systemic · Light chain amyloidosis · Light-chain amyloidosis · primary AL amyloidosis · primary amyloidosis · primary systemic AL amyloidosis · primary systemic amyloidosis · systemic AL amyloidsis

Data availability: 19 GWAS associations (10 studies) · 6 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › AL amyloidosis

Related subtypes (71): congenital nervous system disorder, central nervous system disorder, autoimmune disorder of the nervous system, cranial nerve neuropathy, peripheral nervous system disorder, neuronitis, diplegia of upper limb, retinal disorder, developmental disability, restless legs syndrome, movement disorder, toxic encephalopathy, Barre-Lieou syndrome, Gerstmann syndrome, drug-induced akathisia, drug-induced dyskinesia, stiff-person syndrome, Worster-Drought syndrome, corneal-cerebellar syndrome, pachygyria-intellectual disability-epilepsy syndrome, porencephaly-cerebellar hypoplasia-internal malformations syndrome, symmetrical thalamic calcifications, neonatal brainstem dysfunction, primary orthostatic hypotension, rippling muscle disease with myasthenia gravis, periodic paralysis, qualitative or quantitative protein defects in neuromuscular diseases, specific learning disability, cerebellar hypoplasia-tapetoretinal degeneration syndrome, locked-in syndrome, dopa-responsive dystonia, idiopathic recurrent stupor, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, spontaneous periodic hypothermia, Sydenham chorea, duplication of the pituitary gland, Balint syndrome, paraneoplastic neurologic syndrome, persistent idiopathic facial pain, serotonin syndrome, hypothalamic adipsic hypernatraemia syndrome, exercise-induced malignant hyperthermia, perineural cyst, neuromuscular disease, neuromyelitis optica, AA amyloidosis, neuroleptic malignant syndrome, infectious disorder of the nervous system, central nervous system malformation, synaptopathy, nervous system neoplasm, sensory ganglionopathy, radiculitis, wet beriberi, perceptual disorders, prepubertal anorexia nervosa, neurocutaneous syndrome, neurovascular disorder, Wallerian degeneration, nervous system injury, neurosarcoidosis, neuroendocrine disorder, tubulinopathy, atactic disorder, hereditary neurological disease, meningitis-retention syndrome, KIF1A related neurological disorder, neurological pain disorder, neurodevelopmental disorder, post 5-alpha-reductase inhibitors treatment syndrome, post-selective serotonin reuptake inhibitor sexual dysfunction

Subtypes (2): primary systemic amyloidosis, primary localized amyloidosis

Genetics & variants

GWAS landscape

19 GWAS associations across 10 studies. Top hits map to 12 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs9344	2e-12	CCND1	G	1.62
rs4487645	2e-09	DNAH11	C	1.35
rs7820212	2e-08	ST18 - ALKAL1	A	1.86
rs6752376	3e-08	SILC1 - LINC01247	T	1.54
rs10507419	3e-08	LINC00457, LINC02343	A	1.57
rs79419269	5e-08	CHPF2, SMARCD3	C	1.41
rs1005300	8e-08	CBX7	G	1.29
rs10799599	1e-06	PLA2G2E - RN7SL304P	C	1.26
rs11219122	2e-06	GRAMD1B	C	1.25
rs4792800	2e-06	TNFRSF13B	G	1.36
rs142802669	3e-06	ULK4	C	1.3
rs2273156	3e-06	SRP54-AS1	C	1.29
rs35629860	4e-06	FBRS	A	1.26

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST004028	da Silva Filho MI	2016	1,229	7,526	Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: comparison with myeloma.
GCST004812	Meziane I	2017	844	0	Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts.
GCST004805	Meziane I	2017	835	0	Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts.
GCST004811	Meziane I	2017	535	0	Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts.
GCST004808	Meziane I	2017	447	0	Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts.
GCST004806	Meziane I	2017	426	0	Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts.
GCST004804	Meziane I	2017	404	0	Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts.
GCST004809	Meziane I	2017	345	0	Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts.
GCST004807	Meziane I	2017	194	0	Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts.
GCST004810	Meziane I	2017	85	0	Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	1
Tier 4: intronic/intergenic	11

MAF distribution

Bucket	Variants
common (>=0.05)	13
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	10
splice_region_variant	1
intergenic_variant	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs9344	11	69648142	G>A	0.05	splice_region_variant	CCND1	2e-12	Tier 2: splice/UTR
rs4487645	7	21898622	C>A,G,T	0.33	intron_variant	DNAH11	2e-09	Tier 4: intronic/intergenic
rs7820212	8	52506268	T>A	0.05	intergenic_variant	ST18 - ALKAL1	2e-08	Tier 4: intronic/intergenic
rs6752376	2	6303084	C>A,T	0.05	intron_variant	SILC1 - LINC01247	3e-08	Tier 4: intronic/intergenic
rs10507419	13	34612315	T>A	0.05	intron_variant	LINC00457, LINC02343	3e-08	Tier 4: intronic/intergenic
rs79419269	7	151239990	T>C	0.12	intron_variant	CHPF2, SMARCD3	5e-08	Tier 4: intronic/intergenic
rs1005300	22	39151886	C>G	0.41	intron_variant	CBX7	8e-08	Tier 4: intronic/intergenic
rs10799599	1	19968007	C>G	0.38	regulatory_region_variant	PLA2G2E - RN7SL304P	1e-06	Tier 3: regulatory
rs11219122	11	123369465	T>A,C	0.35	intron_variant	GRAMD1B	2e-06	Tier 4: intronic/intergenic
rs4792800	17	16941853	A>G	0.12	intron_variant	TNFRSF13B	2e-06	Tier 4: intronic/intergenic
rs142802669	3	41827935		0.17	intron_variant	ULK4	3e-06	Tier 4: intronic/intergenic
rs2273156	14	34969593	T>A,C	0.19	intron_variant	SRP54-AS1	3e-06	Tier 4: intronic/intergenic
rs35629860	16	30660211	G>A,C	0.26	intron_variant	FBRS	4e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SRP54	Orphanet:675767	Severe congenital neutropenia-developmental delay syndrome due to SRP54 deficiency
CCND1	Orphanet:29073	Multiple myeloma
CCND1	Orphanet:52416	Mantle cell lymphoma
CCND1	Orphanet:67038	B-cell chronic lymphocytic leukemia
CCND1	Orphanet:892	Von Hippel-Lindau disease
SRCAP	Orphanet:2044	Floating-Harbor syndrome
SRCAP	Orphanet:528084	Non-specific syndromic intellectual disability
TNFRSF13B	Orphanet:696907	Common variable immunodeficiency phenotype due to homozygous TACI deficiency
NBEA	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability

Cohort genes → proteins

18 cohort genes, 15 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	18

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BCL7C	HGNC:1006	ENSG00000099385	Q8WUZ0	B-cell CLL/lymphoma 7 protein family member C	gwas
SMARCD3	HGNC:11108	ENSG00000082014	Q6STE5	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3	gwas
SRP54	HGNC:11301	ENSG00000100883	P61011	Signal recognition particle subunit SRP54	gwas
CBX7	HGNC:1557	ENSG00000100307	O95931	Chromobox protein homolog 7	gwas
RB1CC1	HGNC:15574	ENSG00000023287	Q8TDY2	RB1-inducible coiled-coil protein 1	gwas
ULK4	HGNC:15784	ENSG00000168038	Q96C45	Serine/threonine-protein kinase ULK4	gwas
CCND1	HGNC:1582	ENSG00000110092	P24385	G1/S-specific cyclin-D1	gwas
RNF40	HGNC:16867	ENSG00000103549	O75150	E3 ubiquitin-protein ligase BRE1B	gwas
SRCAP	HGNC:16974	ENSG00000080603	Q6ZRS2	Chromatin remodeling protein SRCAP	gwas
TNFRSF13B	HGNC:18153	ENSG00000240505	O14836	Tumor necrosis factor receptor superfamily member 13B	gwas
FBRS	HGNC:20442	ENSG00000156860	Q9HAH7	Probable fibrosin-1	gwas
PRR14	HGNC:28458	ENSG00000156858	Q9BWN1	Proline-rich protein 14	gwas
ALKAL1	HGNC:33775	ENSG00000196711	Q6UXT8	ALK and LTK ligand 1	gwas
MIR4493	HGNC:41778	ENSG00000265357		microRNA 4493	gwas
LINC00457	HGNC:42805	ENSG00000225179		long intergenic non-protein coding RNA 457	gwas
LINC01247	HGNC:49841	ENSG00000227007		long intergenic non-protein coding RNA 1247	gwas
NBEA	HGNC:7648	ENSG00000172915	Q8NFP9	Neurobeachin	gwas
PLA2G2A	HGNC:9031	ENSG00000188257	P14555	Phospholipase A2, membrane associated	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCL7C	B-cell CLL/lymphoma 7 protein family member C	May play an anti-apoptotic role.
SMARCD3	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SRP54	Signal recognition particle subunit SRP54	Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER).
CBX7	Chromobox protein homolog 7	Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development.
RB1CC1	RB1-inducible coiled-coil protein 1	Involved in autophagy.
ULK4	Serine/threonine-protein kinase ULK4	May be involved in the remodeling of cytoskeletal components, such as alpha-tubulin, and in this way regulates neurite branching and elongation, as well as cell motility.
CCND1	G1/S-specific cyclin-D1	Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition.
RNF40	E3 ubiquitin-protein ligase BRE1B	Component of the RNF20/40 E3 ubiquitin-protein ligase complex that mediates monoubiquitination of ‘Lys-120’ of histone H2B (H2BK120ub1).
SRCAP	Chromatin remodeling protein SRCAP	Acts both as a chromatin remodeler and transcription coregulator.
TNFRSF13B	Tumor necrosis factor receptor superfamily member 13B	Receptor for TNFSF13/APRIL and TNFSF13B/TALL1/BAFF/BLYS that binds both ligands with similar high affinity.
PRR14	Proline-rich protein 14	Functions in tethering peripheral heterochromatin to the nuclear lamina during interphase, possibly through the interaction with heterochromatin protein CBX5/HP1 alpha.
ALKAL1	ALK and LTK ligand 1	Cytokine that acts as a physiological ligand for receptor tyrosine kinase LTK, leading to its activation.
NBEA	Neurobeachin	Binds to type II regulatory subunits of protein kinase A and anchors/targets them to the membrane.
PLA2G2A	Phospholipase A2, membrane associated	Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids with implications in host antimicrobial defense, inflammatory response and tissue regeneration.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 14 · Druggable fraction: 0.11

Family distribution

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

Family	Genes	Fold	FDR
Other/Unknown	14	1.4×	0.237
Kinase	1	1.5×	0.902
Scaffold/PPI	1	1.0×	0.902
Enzyme (other)	1	0.7×	0.902
Transcription factor	1	0.5×	0.902

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCL7C	Other/Unknown	no		BCL7
SMARCD3	Other/Unknown	no		SWIB_MDM2_domain, SWIB_domain, SWIB_MDM2_dom_sf
SRP54	Other/Unknown	no		SRP54_GTPase_dom, AAA+_ATPase, Signal_recog_particle_SRP54_M
CBX7	Other/Unknown	no		Chromo/chromo_shadow_dom, Chromo-like_dom_sf, Chromo_dom_subgr
RB1CC1	Other/Unknown	no		Atg11_C, ATG11
ULK4	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, ARM-like
CCND1	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom
RNF40	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, E3_ubiquit_lig_Bre1
SRCAP	Other/Unknown	no		SNF2_N, Helicase_C-like, Helicase_ATP-bd
TNFRSF13B	Other/Unknown	no		TACI_Cys-rich-dom, TNFR_13B
FBRS	Other/Unknown	no		AUTS2
PRR14	Other/Unknown	no		PRR14, Tantalus-like
ALKAL1	Other/Unknown	no		ALKL1/2
MIR4493	Other/Unknown	no
LINC00457	Other/Unknown	no
LINC01247	Other/Unknown	no
NBEA	Scaffold/PPI	no		BEACH_dom, WD40_rpt, NBEA-like_DUF1088
PLA2G2A	Enzyme (other)	yes	3.1.1.4	PLA2, PLA2-like_dom, PLA2_Asp_AS

Expression context

Cohort genes with no expression data: 0.

14 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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	2
ganglionic eminence	2
right hemisphere of cerebellum	2
buccal mucosa cell	2
stromal cell of endometrium	2
cortical plate	2
left testis	2
granulocyte	2
male germ line stem cell (sensu Vertebrata) in testis	2
blood	2
apex of heart	1
olfactory segment of nasal mucosa	1
nucleus accumbens	1
body of pancreas	1
islet of Langerhans	1
pancreas	1
Brodmann (1909) area 10	1
cerebellar vermis	1
paraflocculus	1
bronchial epithelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCL7C	262	ubiquitous	marker	lower esophagus mucosa, olfactory segment of nasal mucosa, apex of heart
SMARCD3	280	ubiquitous	marker	ganglionic eminence, nucleus accumbens, right hemisphere of cerebellum
SRP54	296	ubiquitous	marker	body of pancreas, pancreas, islet of Langerhans
CBX7	296	ubiquitous	marker	cerebellar vermis, paraflocculus, Brodmann (1909) area 10
RB1CC1	296	ubiquitous	marker	buccal mucosa cell, bronchial epithelial cell, caput epididymis
ULK4	203	ubiquitous	marker	decidua, secondary oocyte, buccal mucosa cell
CCND1	280	ubiquitous	marker	endometrium epithelium, stromal cell of endometrium, upper arm skin
RNF40	235	ubiquitous	marker	ventricular zone, cortical plate, left testis
SRCAP	167	ubiquitous	yes	sural nerve, stromal cell of endometrium, granulocyte
TNFRSF13B	158	tissue_specific	marker	type B pancreatic cell, olfactory bulb, spleen
FBRS	287	ubiquitous	marker	left testis, right testis, lower esophagus mucosa
PRR14	282	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar cortex
ALKAL1	76	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, gall bladder
MIR4493	21		yes	adrenal tissue, blood, right frontal lobe
LINC00457	88		yes	male germ line stem cell (sensu Vertebrata) in testis, tonsil, ganglionic eminence
LINC01247	2		marker	blood, dorsolateral prefrontal cortex
NBEA	265	ubiquitous	marker	cortical plate, pigmented layer of retina, pons
PLA2G2A	220	broad	marker	palpebral conjunctiva, pericardium, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCND1	8,328
RB1CC1	3,031
RNF40	3,001
SRCAP	2,987
SMARCD3	2,091
PLA2G2A	1,616
FBRS	1,350
NBEA	1,345
TNFRSF13B	1,333
CBX7	1,287

Intra-cohort edges

A	B	Sources
BCL7C	SMARCD3	biogrid_interaction, intact

Structural data

PDB: 11 · AlphaFold-only: 4 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RB1CC1	Q8TDY2	18
PLA2G2A	P14555	17
CCND1	P24385	11
SRCAP	Q6ZRS2	10
SRP54	P61011	9
CBX7	O95931	8
RNF40	O75150	4
ALKAL1	Q6UXT8	3
ULK4	Q96C45	2
TNFRSF13B	O14836	2
NBEA	Q8NFP9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMARCD3	Q6STE5	80.99
BCL7C	Q8WUZ0	63.71
PRR14	Q9BWN1	55.62
FBRS	Q9HAH7	52.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 121. Enrichment computed across 18 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MITF-M-dependent gene expression	3	54.4×	0.002	BCL7C, SMARCD3, CCND1
Formation of the non-canonical BAF (ncBAF) complex	2	134.3×	0.003	BCL7C, SMARCD3
Formation of the polybromo-BAF (pBAF) complex	2	126.9×	0.003	BCL7C, SMARCD3
Formation of the embryonic stem cell BAF (esBAF) complex	2	120.2×	0.003	BCL7C, SMARCD3
MITF-M-regulated melanocyte development	3	34.3×	0.003	BCL7C, SMARCD3, CCND1
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	2	91.4×	0.004	BCL7C, SMARCD3
Regulation of endogenous retroelements	2	73.7×	0.005	BCL7C, SMARCD3
Regulation of MITF-M-dependent genes involved in pigmentation	2	53.1×	0.009	BCL7C, SMARCD3
Signaling by NOTCH	2	35.1×	0.019	CCND1, NBEA
RMTs methylate histone arginines	2	29.3×	0.022	SMARCD3, CCND1
Transcriptional regulation by RUNX1	2	29.3×	0.022	SMARCD3, CCND1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	2	23.6×	0.031	BCL7C, SMARCD3
Drug-mediated inhibition of CDK4/CDK6 activity	1	228.4×	0.041	CCND1
PTK6 Regulates Cell Cycle	1	190.3×	0.045	CCND1
Chromatin organization	2	16.3×	0.051	SMARCD3, CCND1
RUNX3 regulates WNT signaling	1	114.2×	0.056	CCND1
RUNX3 regulates p14-ARF	1	114.2×	0.056	CCND1
Chromatin modifying enzymes	2	14.5×	0.056	SMARCD3, CCND1
Epigenetic regulation of gene expression	2	14.3×	0.056	BCL7C, SMARCD3
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	1	87.8×	0.063	CCND1
Signaling by LTK	1	87.8×	0.063	ALKAL1
Protein ubiquitination	1	81.6×	0.063	RNF40
R-HSA-1368082	1	71.4×	0.063	SMARCD3
Acyl chain remodelling of PI	1	67.2×	0.063	PLA2G2A
Regulation of RUNX1 Expression and Activity	1	67.2×	0.063	CCND1
Acyl chain remodelling of PG	1	63.4×	0.063	PLA2G2A
PKA activation	1	63.4×	0.063	NBEA
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	1	63.4×	0.063	CCND1
Formation of the canonical BAF (cBAF) complex	1	63.4×	0.063	BCL7C
PKA-mediated phosphorylation of CREB	1	57.1×	0.063	NBEA

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of G0 to G1 transition	2	96.3×	0.010	BCL7C, SMARCD3
positive regulation of G2/M transition of mitotic cell cycle	2	86.0×	0.010	SMARCD3, CCND1
regulation of nucleotide-excision repair	2	86.0×	0.010	BCL7C, SMARCD3
regulation of mitotic metaphase/anaphase transition	2	70.8×	0.011	BCL7C, SMARCD3
protein kinase C deactivation	1	1203.7×	0.013	ULK4
regulation of neutrophil activation	1	1203.7×	0.013	PLA2G2A
positive regulation of double-strand break repair	2	49.1×	0.013	BCL7C, SMARCD3
regulation of G1/S transition of mitotic cell cycle	2	43.8×	0.013	BCL7C, SMARCD3
chromatin remodeling	3	15.6×	0.013	BCL7C, SMARCD3, SRCAP
ribophagy	1	601.9×	0.018	RB1CC1
positive regulation of ERK5 cascade	1	601.9×	0.018	ALKAL1
re-entry into mitotic cell cycle	1	401.2×	0.025	CCND1
cardiac right ventricle formation	1	300.9×	0.027	SMARCD3
SRP-dependent cotranslational protein targeting to membrane, signal sequence recognition	1	300.9×	0.027	SRP54
response to UV-A	1	300.9×	0.027	CCND1
phosphatidylethanolamine metabolic process	1	240.7×	0.032	PLA2G2A
response to vitamin E	1	200.6×	0.032	CCND1
positive regulation of mammary gland epithelial cell proliferation	1	200.6×	0.032	CCND1
phosphatidic acid metabolic process	1	200.6×	0.032	PLA2G2A
intestinal stem cell homeostasis	1	172.0×	0.032	PLA2G2A
response to leptin	1	172.0×	0.032	CCND1
regulation of p38MAPK cascade	1	172.0×	0.032	ULK4
SRP-dependent cotranslational protein targeting to membrane	1	150.5×	0.034	SRP54
SRP-dependent cotranslational protein targeting to membrane, translocation	1	150.5×	0.034	SRP54
positive regulation of smooth muscle cell differentiation	1	133.8×	0.036	SMARCD3
exocrine pancreas development	1	120.4×	0.036	SRP54
secondary heart field specification	1	109.4×	0.036	SMARCD3
mammary gland epithelial cell proliferation	1	109.4×	0.036	CCND1
angiotensin-activated signaling pathway	1	109.4×	0.036	PLA2G2A
response to magnesium ion	1	100.3×	0.036	CCND1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 15

Druggability breadth: 4 of 18 evidence-associated genes (22%) 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
CCND1	PALBOCICLIB
PLA2G2A	DEXAMETHASONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCND1	35	4
PLA2G2A	2	4
CBX7	1	3
BCL7C	0	0
SMARCD3	0	0
SRP54	0	0
RB1CC1	0	0
ULK4	0	0
RNF40	0	0
SRCAP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	CCND1
ABEMACICLIB	4	CCND1
RIBOCICLIB	4	CCND1
TRILACICLIB	4	CCND1
DEXAMETHASONE	4	PLA2G2A
SURAMIN	3	CBX7
DINACICLIB	3	CCND1
LEROCICLIB	3	CCND1
ALVOCIDIB	3	CCND1
QUERCETIN	3	CCND1
INDIRUBIN	2	CCND1
SELICICLIB	2	CCND1
REBASTINIB	2	CCND1
NARAZACICLIB	2	CCND1
RIVICICLIB	2	CCND1
RG-547	2	CCND1
VORUCICLIB	2	CCND1
ULECACICLIB	2	CCND1
CROZBACICLIB	2	CCND1
RONICICLIB	2	CCND1
EBVACICLIB	2	CCND1
AT-7519	2	CCND1
ECIRUCICLIB	2	CCND1
CULMERCICLIB	2	CCND1
ATIRMOCICLIB	2	CCND1
ISTISOCICLIB	2	CCND1
TEGTOCICLIB	2	CCND1
MILCICLIB	2	CCND1
ELLAGIC ACID	2	CCND1
VARESPLADIB	2	PLA2G2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CCND1	576	Binding:574, Functional:1, ADMET:1
PLA2G2A	111	Binding:100, Functional:11
CBX7	36	Binding:35, Functional:1
SRP54	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLA2G2A	3.1.1.4	phospholipase A2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CCND1	576
PLA2G2A	111

Pharmacogenomics

Cohort genes with a PharmGKB record: 15; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
PALBOCICLIB	4	CCND1
ABEMACICLIB	4	CCND1
RIBOCICLIB	4	CCND1
TRILACICLIB	4	CCND1
SURAMIN	3	CBX7
DINACICLIB	3	CCND1
LEROCICLIB	3	CCND1
ALVOCIDIB	3	CCND1
QUERCETIN	3	CCND1
INDIRUBIN	2	CCND1
SELICICLIB	2	CCND1
REBASTINIB	2	CCND1
NARAZACICLIB	2	CCND1
RIVICICLIB	2	CCND1
RG-547	2	CCND1
VORUCICLIB	2	CCND1
ULECACICLIB	2	CCND1
CROZBACICLIB	2	CCND1
RONICICLIB	2	CCND1
EBVACICLIB	2	CCND1
AT-7519	2	CCND1
ECIRUCICLIB	2	CCND1
CULMERCICLIB	2	CCND1
ATIRMOCICLIB	2	CCND1
ISTISOCICLIB	2	CCND1
TEGTOCICLIB	2	CCND1
MILCICLIB	2	CCND1
ELLAGIC ACID	2	CCND1
VARESPLADIB	2	PLA2G2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CCND1, PLA2G2A
B	Phased (≥1) drug, not yet approved	1	CBX7
C	Druggable family + PDB, no drug	1	ULK4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	14	BCL7C, SMARCD3, SRP54, RB1CC1, RNF40, SRCAP, TNFRSF13B, FBRS, PRR14, ALKAL1 (+4 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BCL7C	0	—
SMARCD3	0	—
SRP54	2	—
RB1CC1	0	—
ULK4	0	—
RNF40	0	—
SRCAP	0	—
TNFRSF13B	0	—
FBRS	0	—
PRR14	0	—
ALKAL1	0	—
MIR4493	0	—
LINC00457	0	—
LINC01247	0	—
NBEA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 109.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	34
Not specified	33
PHASE1	16
PHASE1/PHASE2	13
PHASE3	10
EARLY_PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04504825	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIb AL Amyloidosis (CARES)
NCT04512235	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIa AL Amyloidosis (CARES)
NCT05184088	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy of [18F]Florbetaben PET for Diagnosis of Cardiac AL Amyloidosis
NCT06022939	PHASE3	RECRUITING	Comparing Dara-VCD Chemotherapy Plus Stem Cell Transplant to Dara-VCD Chemotherapy Alone for People Who Have Newly Diagnosed AL Amyloidosis
NCT00344526	PHASE3	COMPLETED	Intensive Versus Conventional Treatment in Patients With Primary Amyloidosis
NCT01078454	PHASE3	COMPLETED	Melphalan and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Systemic Light-Chain Amyloidosis
NCT01277016	PHASE3	COMPLETED	A Trial for Systemic Light-chain (AL) Amyloidosis
NCT02312206	PHASE3	TERMINATED	The VITAL Amyloidosis Study, a Global Phase 3, Efficacy and Safety Study of NEOD001 in Patients With AL Amyloidosis
NCT02489500	PHASE3	TERMINATED	Trial of High Dose Melphalan/Stem Cell Transplant With or Without Bortezomib
NCT04973137	PHASE3	TERMINATED	A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis
NCT03315026	PHASE2	ACTIVE_NOT_RECRUITING	Siltuximab to Decrease Symptom Burden After Autologous Stem Cell Transplantation for Patients With Multiple Myeloma and AL Amyloidosis
NCT03618537	PHASE2	ACTIVE_NOT_RECRUITING	Ixazomib Maintenance Study in Patients With AL Amyloidosis
NCT04270175	PHASE2	ACTIVE_NOT_RECRUITING	Daratumumab, Pomalidomide, and Dexamethasone (DPd) in Relapsed/Refractory Light Chain Amyloidosis Patients Previously Exposed to Daratumumab
NCT05145816	PHASE1/PHASE2	RECRUITING	Phase 1/2a Study of Belantamab Mafodotin in Relapsed or Refractory AL Amyloidosis
NCT05451771	PHASE1/PHASE2	RECRUITING	Venetoclax-Dexamethasone in Relapsed and/or Refractory t(11;14) Amyloidosis
NCT05898646	PHASE2	RECRUITING	Daratumumab Maintenance Therapy for Improving Survival in Patients With Light Chain Amyloidosis, EMILIA Trial
NCT05996406	PHASE2	ACTIVE_NOT_RECRUITING	Venetoclax and Dexamethasone for Newly Diagnosed Light-Chain Amyloidosis with Translocation (11;14)
NCT06097832	PHASE1/PHASE2	RECRUITING	Study of NXC-201 CAR-T in Patients With Light Chain (AL) Amyloidosis
NCT06569147	PHASE1/PHASE2	RECRUITING	Elranatamab in Patients With Relapsed or Refractory AL Amyloidosis
NCT06629818	PHASE2	RECRUITING	Daratumumab Combined With Venetoclax and Dexamethasone for Newly Diagnosed Light-Chain Amyloidosis With Translocation (11;14)
NCT06649695	PHASE2	RECRUITING	A Phase II Trial of Teclistamab in Participants With Previously Treated Immunoglobulin Light-chain (AL) Amyloidosis
NCT06935162	PHASE2	RECRUITING	Teclistamab in Previously Treated AL Amyloidosis
NCT06971380	PHASE2	RECRUITING	Study of HBI0101 (NXC-201) CAR-T Therapy in Multiple Myeloma and Light-Chain Amyloidosis
NCT07039578	PHASE2	RECRUITING	Study Evaluating the Efficacy and Safety of CM336 Injection in the Treatment of Light-Chain Amyloidosis
NCT07055724	PHASE2	NOT_YET_RECRUITING	Study of Eque-cel CAR-T Therapy in Newly Diagnosed Severe AL Amyloidosis
NCT07079423	PHASE2	RECRUITING	Teclistamab in Newly Diagnosed Mayo Stage IIIB AL Amyloidosis
NCT07081646	PHASE1/PHASE2	RECRUITING	A Phase 1b/2 Study of CAR T Cell Therapy Targeting CD19 and BCMA in Participants With Relapsed or Refractory AL Amyloidosis.
NCT07335887	PHASE2	NOT_YET_RECRUITING	Sonrotoclax Plus Dexamethasone With or Without Daratumumab Regimen in Patients With t(11;14) Primary AL Amyloidosis
NCT00006251	PHASE1/PHASE2	COMPLETED	Fludarabine Phosphate, Low-Dose Total-Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine, Mycophenolate Mofetil, Donor Lymphocyte Infusion in Treating Patients With Hematopoietic Cancer
NCT00224393	PHASE2	COMPLETED	Phase II Trial of Enbrel in Patients With Primary Systemic Amyloidosis
NCT00520767	PHASE2	COMPLETED	Bortezomib, Melphalan, and Dexamethasone in Treating Patients With Primary Amyloidosis or Light Chain Deposition Disease
NCT00651937	PHASE2	COMPLETED	Trial of Two Stem Cell Doses To Reduce Transplant Induced Symptom Burden
NCT00883623	PHASE2	COMPLETED	A Trial of Treatment With Lenalidomide-Melphalan-Dexamethasone in Patients With Primary (AL) Amyloidosis
NCT01072773	PHASE2	COMPLETED	Bortezomib, Cyclophosphamide, and Dexamethasone in Treating Patients With Primary Systemic Light Chain Amyloidosis
NCT01194791	PHASE2	COMPLETED	Lendexal in Patients With Primary Systemic Amyloidosis (AL) Newly Diagnosed
NCT01222260	PHASE2	COMPLETED	Bendamustine and Dexamethasone in Patients With Relapsed AL Amyloidosis
NCT01570387	PHASE1/PHASE2	COMPLETED	A Phase I/II Trial of Pomalidomide and Dexamethasone in Subjects With Previously-Treated AL Amyloidosis
NCT01707264	PHASE1/PHASE2	COMPLETED	Phase 1/2, Open Label, Dose Escalation Study of NEOD001 in Subjects With Light Chain (AL) Amyloidosis
NCT01849783	PHASE2	COMPLETED	Autologous Stem Cell Transplant Followed By Maintenance Therapy in Treating Elderly Patients With Multiple Myeloma
NCT02015312	PHASE2	COMPLETED	A Trial for the Treatment of Cardiac AL-Amyloidosis With the Green Tea Compound Epigallocatechin-3-gallate (TAME-AL)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEXAMETHASONE	4	27
TECLISTAMAB	4	5
FOSCARNET	4	4
ISATUXIMAB	4	4
MELPHALAN	4	4
BELANTAMAB MAFODOTIN	4	2
BORTEZOMIB	4	2
DARATUMUMAB	4	2
ELRANATAMAB	4	2
FLORBETABEN F18	4	2
BENDAMUSTINE	4	1
CILTACABTAGENE AUTOLEUCEL	4	1
ELOTUZUMAB	4	1
GANCICLOVIR	4	1
HYALURONIDASE (HUMAN RECOMBINANT)	4	1
IDECABTAGENE VICLEUCEL	4	1
IXAZOMIB CITRATE	4	1
POMALIDOMIDE	4	1
SILTUXIMAB	4	1
TALQUETAMAB	4	1
VALGANCICLOVIR	4	1
BIRTAMIMAB	3	6
IXAZOMIB	3	5
ANSELAMIMAB	3	4
EPIGALOCATECHIN GALLATE	3	1
SONROTOCLAX	3	1
CHEMBL2093113	0	1
CHEMBL1813256	0	1