Autoimmune lymphoproliferative syndrome type 4

Summary

Autoimmune lymphoproliferative syndrome type 4 (MONDO:0013767) is a disease caused by KRAS (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KRAS (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune lymphoproliferative syndrome type 4
Mondo ID	MONDO:0013767
OMIM	614470
Orphanet	268114
DOID	DOID:0110117
SNOMED CT	723508002
UMLS	C2674723
MedGen	382434
GARD	0017262
Is cancer (heuristic)	no

Also known as: ALPS4 · autoimmune lymphoproliferative syndrome caused by mutation in NRAS · NRAS autoimmune lymphoproliferative syndrome · RALD · RAS-associated autoimmune leukoproliferative disease · RAS-associated autoimmune leukoproliferative disorder · RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic

Data availability: 33 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › hypersensitivity reaction disease › type IV hypersensitivity disease › autoimmune lymphoproliferative syndrome › autoimmune lymphoproliferative syndrome type 4

Related subtypes (8): autoimmune lymphoproliferative syndrome type 1, autoimmune lymphoproliferative syndrome type 2A, autoimmune lymphoproliferative syndrome type 2B, autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency, Castleman-Kojima disease, FAS-related autoimmune lymphoproliferative immune disorder, type 3 autoimmune lymphoproliferative syndrome, autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD

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

33 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 9 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 4 likely benign, 2 pathogenic, 2 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12582	NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12587	NM_004985.5(KRAS):c.458A>T (p.Asp153Val)	KRAS	Pathogenic	reviewed by expert panel
12590	NM_004985.5(KRAS):c.101C>G (p.Pro34Arg)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375963	NM_033360.4(KRAS):c.436G>C (p.Ala146Pro)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40452	NM_004985.5(KRAS):c.65A>G (p.Gln22Arg)	KRAS	Pathogenic	reviewed by expert panel
45122	NM_004985.5(KRAS):c.35G>C (p.Gly12Ala)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
45123	NM_004985.5(KRAS):c.37G>T (p.Gly13Cys)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13901	NM_002524.5(NRAS):c.38G>A (p.Gly13Asp)	NRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219097	NM_002524.5(NRAS):c.35G>C (p.Gly12Ala)	NRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39648	NM_002524.5(NRAS):c.35G>A (p.Gly12Asp)	NRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40470	NM_002524.5(NRAS):c.35G>T (p.Gly12Val)	NRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40460	NM_033360.4(KRAS):c.355G>A (p.Asp119Asn)	KRAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
180857	NM_004985.5(KRAS):c.184GAG[1] (p.Glu63del)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2454057	NM_004985.5(KRAS):c.168C>T (p.Leu56=)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
503538	NM_004985.5(KRAS):c.407G>A (p.Ser136Asn)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
620625	NM_033360.4(KRAS):c.*101_*106del	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626130	NM_033360.4(KRAS):c.112-5C>T	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028518	NM_033360.4(KRAS):c.559A>G (p.Ile187Val)	KRAS	Uncertain significance	criteria provided, single submitter
1046139	NM_004985.5(KRAS):c.388_389delinsAT (p.Ala130Ile)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1047419	NM_004985.5(KRAS):c.352T>C (p.Cys118Arg)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1717054	NM_004985.5(KRAS):c.365C>G (p.Ser122Cys)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
180861	NM_033360.4(KRAS):c.389C>T (p.Ala130Val)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1915455	NM_004985.5(KRAS):c.450+5G>A	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2909102	NM_004985.5(KRAS):c.331A>G (p.Met111Val)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3574545	NM_004985.5(KRAS):c.451-6T>C	KRAS	Uncertain significance	criteria provided, single submitter
935432	NM_004985.5(KRAS):c.487A>G (p.Ile163Val)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
477662	NM_002524.5(NRAS):c.25G>A (p.Val9Ile)	NRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
138061	NM_033360.4(KRAS):c.90C>T (p.Asp30=)	KRAS	Likely benign	reviewed by expert panel
177714	NM_004985.5(KRAS):c.112-9C>T	KRAS	Likely benign	criteria provided, multiple submitters, no conflicts
180052	NM_004985.5(KRAS):c.451-5652C>T	KRAS	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 18 · 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
KRAS	Strong	Autosomal dominant	autoimmune lymphoproliferative syndrome type 4	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
KRAS	Orphanet:3339	Oculoectodermal syndrome
KRAS	Orphanet:648	Noonan syndrome
KRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
NRAS	Orphanet:146	Differentiated thyroid carcinoma
NRAS	Orphanet:2612	Linear nevus sebaceus syndrome
NRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
NRAS	Orphanet:389	Langerhans cell histiocytosis
NRAS	Orphanet:626	Large/giant congenital melanocytic nevus
NRAS	Orphanet:648	Noonan syndrome
NRAS	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	gencc,clinvar
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.

Protein-family classification

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

Family distribution

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

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
nipple	1
pylorus	1
trigeminal ganglion	1
epithelium of nasopharynx	1
gingival epithelium	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
NRAS	7,598

Intra-cohort edges

A	B	Sources
KRAS	NRAS	intact

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
NRAS	P01111	35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 72. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by RAS GAP mutants	2	3806.7×	2e-06	KRAS, NRAS
Signaling by RAS GTPase mutants	2	3806.7×	2e-06	KRAS, NRAS
Activation of RAS in B cells	2	2284.0×	4e-06	KRAS, NRAS
RAS signaling downstream of NF1 loss-of-function variants	2	1631.4×	5e-06	KRAS, NRAS
Estrogen-stimulated signaling through PRKCZ	2	1631.4×	5e-06	KRAS, NRAS
SOS-mediated signalling	2	1427.5×	5e-06	KRAS, NRAS
Activated NTRK3 signals through RAS	2	1268.9×	5e-06	KRAS, NRAS
EGFR Transactivation by Gastrin	2	1142.0×	5e-06	KRAS, NRAS
SHC-related events triggered by IGF1R	2	1142.0×	5e-06	KRAS, NRAS
Activated NTRK2 signals through RAS	2	1142.0×	5e-06	KRAS, NRAS
MET activates RAS signaling	2	1038.2×	5e-06	KRAS, NRAS
Signaling by FGFR4 in disease	2	951.7×	5e-06	KRAS, NRAS
Activated NTRK2 signals through FRS2 and FRS3	2	951.7×	5e-06	KRAS, NRAS
Constitutive Signaling by Overexpressed ERBB2	2	951.7×	5e-06	KRAS, NRAS
p38MAPK events	2	878.5×	5e-06	KRAS, NRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	2	878.5×	5e-06	KRAS, NRAS
Signaling by PDGFRA extracellular domain mutants	2	878.5×	5e-06	KRAS, NRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	2	815.7×	6e-06	KRAS, NRAS
GRB2 events in EGFR signaling	2	761.3×	6e-06	KRAS, NRAS
Erythropoietin activates RAS	2	761.3×	6e-06	KRAS, NRAS
Signaling by FLT3 ITD and TKD mutants	2	761.3×	6e-06	KRAS, NRAS
SHC1 events in ERBB4 signaling	2	713.8×	6e-06	KRAS, NRAS
SHC1 events in EGFR signaling	2	713.8×	6e-06	KRAS, NRAS
Constitutive Signaling by EGFRvIII	2	713.8×	6e-06	KRAS, NRAS
Signalling to RAS	2	671.8×	6e-06	KRAS, NRAS
Insulin receptor signalling cascade	2	671.8×	6e-06	KRAS, NRAS
Signaling by ERBB2 ECD mutants	2	671.8×	6e-06	KRAS, NRAS
GRB2 events in ERBB2 signaling	2	634.4×	6e-06	KRAS, NRAS
Tie2 Signaling	2	601.0×	6e-06	KRAS, NRAS
SHC-mediated cascade:FGFR3	2	601.0×	6e-06	KRAS, NRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Ras protein signal transduction	2	205.5×	7e-04	KRAS, NRAS
MAPK cascade	2	153.2×	7e-04	KRAS, NRAS
response to mineralocorticoid	1	8426.0×	0.001	KRAS
forebrain astrocyte development	1	2808.7×	0.003	KRAS
response to isolation stress	1	2106.5×	0.003	KRAS
response to gravity	1	1404.3×	0.004	KRAS
type I pneumocyte differentiation	1	766.0×	0.005	KRAS
myoblast proliferation	1	702.2×	0.005	KRAS
positive regulation of cellular senescence	1	648.1×	0.005	KRAS
negative regulation of epithelial cell differentiation	1	601.9×	0.005	KRAS
regulation of synaptic transmission, GABAergic	1	526.6×	0.005	KRAS
regulation of long-term neuronal synaptic plasticity	1	495.6×	0.005	KRAS
striated muscle cell differentiation	1	495.6×	0.005	KRAS
glial cell proliferation	1	443.5×	0.005	KRAS
epithelial tube branching involved in lung morphogenesis	1	421.3×	0.005	KRAS
positive regulation of glial cell proliferation	1	351.1×	0.006	KRAS
positive regulation of Rac protein signal transduction	1	324.1×	0.006	KRAS
cardiac muscle cell proliferation	1	290.6×	0.006	KRAS
Rac protein signal transduction	1	280.9×	0.006	KRAS
homeostasis of number of cells within a tissue	1	221.7×	0.007	KRAS
skeletal muscle cell differentiation	1	172.0×	0.009	KRAS
response to glucocorticoid	1	162.0×	0.009	KRAS
visual learning	1	153.2×	0.009	KRAS
positive regulation of endothelial cell proliferation	1	115.4×	0.012	NRAS
liver development	1	110.9×	0.012	KRAS
female pregnancy	1	105.3×	0.012	KRAS
neuron apoptotic process	1	92.6×	0.013	KRAS
cytokine-mediated signaling pathway	1	65.3×	0.017	KRAS
negative regulation of neuron apoptotic process	1	55.4×	0.020	KRAS
gene expression	1	39.9×	0.026	KRAS

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
KRAS	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRAS	11	4
NRAS	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS
L-778123 FREE BASE	1	NRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KRAS	861	Binding:829, Functional:32
NRAS	18	Binding:18

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KRAS	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KRAS	861

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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)
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS
L-778123 FREE BASE	1	NRAS

Druggability pyramid

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

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

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.