complement component C1s deficiency

Summary

complement component C1s deficiency (MONDO:0013419) is a disease caused by C1S (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: C1S (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complement component C1s deficiency
Mondo ID	MONDO:0013419
MeSH	C565170
OMIM	613783
UMLS	C3151078
MedGen	462428
GARD	0015707
Is cancer (heuristic)	no

Also known as: C1SD · complement component C1s deficiency

Data availability: 17 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › complement deficiency › classic complement early component deficiency › complement component C1s deficiency

Related subtypes (12): C1 inhibitor deficiency, complement component C1r/C1s deficiency, complement component 2 deficiency, complement component 5 deficiency, complement component 7 deficiency, complement component 6 deficiency, complement component 3 deficiency, type II complement component 8 deficiency, type I complement component 8 deficiency, complement component 9 deficiency, complement component 4b deficiency, complement component 4a deficiency

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

17 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 5 pathogenic, 3 conflicting classifications of pathogenicity, 2 likely benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17067	NM_001734.5(C1S):c.1132_1135del (p.Phe378fs)	C1S	Pathogenic	no assertion criteria provided
1939145	NM_001734.5(C1S):c.1309_1310del (p.Arg437fs)	C1S	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137294	NM_001734.5(C1S):c.1567C>T (p.Arg523Ter)	C1S	Pathogenic	criteria provided, multiple submitters, no conflicts
3336211	NM_001734.5(C1S):c.343del (p.Ser115fs)	C1S	Pathogenic	criteria provided, multiple submitters, no conflicts
4849179	NC_000012.11:g.(7168182_7169142)(7178337?)del	C1S	Pathogenic	criteria provided, single submitter
549852	NM_003482.4(KMT2D):c.8626del (p.Gln2876fs)	KMT2D	Pathogenic	criteria provided, single submitter
1705563	NM_001734.5(C1S):c.1729_1730del (p.Asp577fs)	C1S	Likely pathogenic	criteria provided, single submitter
625899	NM_001734.5(C1S):c.943G>A (p.Asp315Asn)	C1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
806820	NM_001734.5(C1S):c.100A>G (p.Ser34Gly)	C1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
992547	NM_001734.5(C1S):c.1198G>C (p.Glu400Gln)	C1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694448	NM_001734.5(C1S):c.991C>T (p.Arg331Cys)	C1S	Uncertain significance	criteria provided, multiple submitters, no conflicts
17068	NM_001734.5(C1S):c.1600C>T (p.Arg534Trp)	C1S	Uncertain significance	criteria provided, multiple submitters, no conflicts
625898	NM_001734.5(C1S):c.514G>A (p.Gly172Arg)	C1S	Uncertain significance	criteria provided, multiple submitters, no conflicts
830030	NM_001734.5(C1S):c.733C>T (p.Arg245Trp)	C1S	Uncertain significance	criteria provided, multiple submitters, no conflicts
976135	NM_001734.5(C1S):c.1139C>T (p.Ser380Phe)	C1S	Uncertain significance	criteria provided, multiple submitters, no conflicts
1653250	NM_001734.5(C1S):c.622T>C (p.Leu208=)	C1S	Likely benign	criteria provided, multiple submitters, no conflicts
734395	NM_001734.5(C1S):c.979G>C (p.Val327Leu)	C1S	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
C1S	Strong	Autosomal recessive	complement component C1s deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
C1S	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
C1S	Orphanet:75392	Periodontal Ehlers-Danlos syndrome
KMT2D	Orphanet:2322	Kabuki syndrome
KMT2D	Orphanet:589856	Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

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
C1S	HGNC:1247	ENSG00000182326	P09871	Complement C1s subcomponent	gencc,clinvar
KMT2D	HGNC:7133	ENSG00000167548	O14686	Histone-lysine N-methyltransferase 2D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
C1S	Complement C1s subcomponent	Component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the ad…
KMT2D	Histone-lysine N-methyltransferase 2D	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4).

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Protease	1	18.3×	0.108
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C1S	Protease	yes	3.4.21.42	EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, CUB_dom
KMT2D	Transcription factor	no		SET_dom, Znf_RING, Znf_PHD

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
parietal pleura	1
pericardium	1
right lobe of liver	1
buccal mucosa cell	1
medial globus pallidus	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C1S	287	ubiquitous	marker	pericardium, right lobe of liver, parietal pleura
KMT2D	272	ubiquitous	marker	buccal mucosa cell, medial globus pallidus, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KMT2D	3,223
C1S	2,304

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C1S	P09871	14
KMT2D	O14686	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. 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
Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome	1	1142.0×	0.011	KMT2D
Creation of C4 and C2 activators	1	951.7×	0.011	C1S
Classical antibody-mediated complement activation	1	951.7×	0.011	C1S
Complement cascade	1	317.2×	0.021	C1S
Initial triggering of complement	1	300.5×	0.021	C1S
Activation of HOX genes during differentiation	1	219.6×	0.024	KMT2D
Dengue virus activates/modulates innate and adaptive immune responses	1	167.9×	0.026	C1S
Formation of WDR5-containing histone-modifying complexes	1	132.8×	0.026	KMT2D
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.026	KMT2D
Regulation of Complement cascade	1	116.5×	0.026	C1S
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.026	KMT2D
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.026	KMT2D
PKMTs methylate histone lysines	1	80.4×	0.028	KMT2D
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.028	KMT2D
Transcriptional regulation by RUNX1	1	73.2×	0.028	KMT2D
Formation of the beta-catenin:TCF transactivating complex	1	60.1×	0.029	KMT2D
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	60.1×	0.029	KMT2D
TCF dependent signaling in response to WNT	1	58.9×	0.029	KMT2D
Signaling by WNT	1	56.0×	0.029	KMT2D
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	45.7×	0.034	KMT2D
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.034	KMT2D
Chromatin organization	1	40.8×	0.034	KMT2D
Chromatin modifying enzymes	1	36.1×	0.036	KMT2D
Epigenetic regulation of gene expression	1	35.7×	0.036	KMT2D
Innate Immune System	1	12.8×	0.095	C1S
RNA Polymerase II Transcription	1	11.3×	0.104	KMT2D
Gene expression (Transcription)	1	8.9×	0.125	KMT2D
Generic Transcription Pathway	1	7.5×	0.142	KMT2D
Developmental Biology	1	7.2×	0.143	KMT2D
Immune System	1	6.5×	0.153	C1S

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
beta-catenin-TCF complex assembly	1	8426.0×	0.002	KMT2D
oocyte growth	1	2106.5×	0.003	KMT2D
positive regulation of intracellular estrogen receptor signaling pathway	1	601.9×	0.007	KMT2D
complement activation, classical pathway	1	271.8×	0.012	C1S
oogenesis	1	191.5×	0.013	KMT2D
response to estrogen	1	172.0×	0.013	KMT2D
heterochromatin formation	1	127.7×	0.015	KMT2D
methylation	1	85.1×	0.019	KMT2D
proteolysis	1	17.1×	0.068	C1S
positive regulation of cell population proliferation	1	16.8×	0.068	KMT2D
innate immune response	1	16.8×	0.068	C1S
regulation of DNA-templated transcription	1	15.8×	0.068	KMT2D
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	KMT2D

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
C1S	1	3
KMT2D	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NAFAMOSTAT	3	C1S

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
C1S	30	Binding:28, Functional:2
KMT2D	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
C1S	3.4.21.42	complement subcomponent C1s

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

1 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)
NAFAMOSTAT	3	C1S

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	C1S
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KMT2D

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KMT2D	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.