Complement component 6 deficiency

Summary

Complement component 6 deficiency (MONDO:0012908) is a disease caused by C6 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: C6 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 38

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complement component 6 deficiency
Mondo ID	MONDO:0012908
OMIM	612446
DOID	DOID:0060299
UMLS	C2676232
MedGen	436639
GARD	0018291
Is cancer (heuristic)	no

Also known as: C6 classic complement early component deficiency · C6D · classic complement early component deficiency caused by mutation in C6 · complement component 6 deficiency

Data availability: 38 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 6 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 3 deficiency, complement component C1s 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

38 retrieved; paginated sample, class counts are floors:

10 pathogenic/likely pathogenic, 9 uncertain significance, 6 pathogenic, 6 benign/likely benign, 6 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032162	NM_000065.5(C6):c.107C>A (p.Ser36Ter)	C6	Pathogenic	criteria provided, single submitter
12115	NM_000065.5(C6):c.828del (p.Ser277fs)	C6	Pathogenic	criteria provided, single submitter
1323996	NM_000065.5(C6):c.2406_2407del (p.Val802_Phe803insTer)	C6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1355115	NM_000065.5(C6):c.2335_2336del (p.Gln779fs)	C6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458860	NM_000065.5(C6):c.821del (p.Gln274fs)	C6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208565	NM_000065.5(C6):c.1786C>T (p.Arg596Ter)	C6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2418534	NM_000065.5(C6):c.654T>A (p.Cys218Ter)	C6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2671945	NM_000065.5(C6):c.1628_1629dup (p.Gln544fs)	C6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2894375	NM_000065.5(C6):c.1352dup (p.Tyr451Ter)	C6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2906086	NM_000065.5(C6):c.1816C>T (p.Arg606Ter)	C6	Pathogenic	criteria provided, multiple submitters, no conflicts
29922	NM_000065.5(C6):c.237del (p.Ile80fs)	C6	Pathogenic	no assertion criteria provided
505659	NM_000065.5(C6):c.1879del (p.Asp627fs)	C6	Pathogenic	criteria provided, multiple submitters, no conflicts
800939	NM_000065.5(C6):c.2049C>G (p.Tyr683Ter)	C6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
997513	NM_000065.5(C6):c.1138del (p.Gln380fs)	C6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17038	NM_000066.4(C8B):c.1282C>T (p.Arg428Ter)	C8B	Pathogenic	criteria provided, multiple submitters, no conflicts
35594	NM_000066.4(C8B):c.271C>T (p.Gln91Ter)	C8B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675134	NM_000065.5(C6):c.928-1G>C	C6	Likely pathogenic	criteria provided, single submitter
2572986	NM_000065.5(C6):c.2101C>A (p.Arg701=)	C6	Likely pathogenic	criteria provided, single submitter
3065714	NM_000065.5(C6):c.2624-1G>A	C6	Likely pathogenic	criteria provided, single submitter
3592690	NM_000065.5(C6):c.1628_1629del (p.Cys543fs)	C6	Likely pathogenic	criteria provided, single submitter
3779471	NM_000065.5(C6):c.270del (p.Trp90fs)	C6	Likely pathogenic	criteria provided, single submitter
3779472	NM_000065.5(C6):c.2511_2515del (p.Cys837_Asp839delinsTer)	C6	Likely pathogenic	criteria provided, single submitter
379370	NM_000065.5(C6):c.2381+2T>C	C6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063493	NM_000065.5(C6):c.2273C>T (p.Ser758Phe)	C6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1374116	NM_000065.5(C6):c.1219C>T (p.Arg407Cys)	C6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1382094	NM_000065.5(C6):c.2101C>T (p.Arg701Trp)	C6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1423647	NM_000065.5(C6):c.1927G>A (p.Gly643Arg)	C6	Uncertain significance	criteria provided, multiple submitters, no conflicts
3362687	NM_000065.5(C6):c.446G>A (p.Gly149Asp)	C6	Uncertain significance	criteria provided, single submitter
636397	NM_000065.5(C6):c.955G>A (p.Val319Met)	C6	Uncertain significance	criteria provided, multiple submitters, no conflicts
809752	NM_000065.5(C6):c.1999G>C (p.Asp667His)	C6	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
C6	Strong	Autosomal recessive	complement component 6 deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
C6	Orphanet:169150	Immunodeficiency due to a late component of complement deficiency
C8B	Orphanet:169150	Immunodeficiency due to a late component of complement deficiency

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
C6	HGNC:1339	ENSG00000039537	P13671	Complement component C6	gencc,clinvar
C8B	HGNC:1353	ENSG00000021852	P07358	Complement component C8 beta chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
C6	Complement component C6	Component of the membrane attack complex (MAC), a multiprotein complex activated by the complement cascade, which inserts into a target cell membrane and forms a pore, leading to target cell membrane rupture and cell lysis.
C8B	Complement component C8 beta chain	Component of the membrane attack complex (MAC), a multiprotein complex activated by the complement cascade, which inserts into a target cell membrane and forms a pore, leading to target cell membrane rupture and cell lysis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Complement	2	268.0×	1e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C6	Complement	yes		Sushi_SCR_CCP_dom, TSP1_rpt, MAC_perforin
C8B	Complement	yes		TSP1_rpt, MAC_perforin, LDrepeatLR_classA_rpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
liver	2
right lobe of liver	2
heart right ventricle	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C6	173	tissue_specific	marker	right lobe of liver, liver, heart right ventricle
C8B	95	tissue_specific	yes	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C8B	810
C6	738

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C6	P13671	11
C8B	P07358	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Terminal pathway of complement	2	1427.5×	9e-07	C6, C8B
Regulation of Complement cascade	2	233.1×	2e-05	C6, C8B

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
complement activation, GZMK pathway	2	1296.3×	6e-06	C6, C8B
complement activation	2	624.1×	1e-05	C6, C8B
complement activation, classical pathway	2	543.6×	1e-05	C6, C8B
positive regulation of immune response	2	481.5×	1e-05	C6, C8B
killing of cells of another organism	2	271.8×	3e-05	C6, C8B
transmembrane transport	2	168.5×	6e-05	C6, C8B
positive regulation of activation of membrane attack complex	1	2808.7×	6e-04	C6
complement activation, alternative pathway	1	495.6×	0.003	C8B
positive regulation of angiogenesis	1	57.7×	0.021	C6
in utero embryonic development	1	36.0×	0.030	C6
immune response	1	23.5×	0.042	C8B

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
C6	0	0
C8B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

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	0
C	Druggable family + PDB, no drug	2	C6, C8B
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
C6	0	—
C8B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.