type I complement component 8 deficiency

Summary

type I complement component 8 deficiency (MONDO:0013422) is a disease caused by C8A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: C8A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	type I complement component 8 deficiency
Mondo ID	MONDO:0013422
OMIM	613790
DOID	DOID:0060301
UMLS	C3151081
MedGen	462431
GARD	0010626
Is cancer (heuristic)	no

Also known as: C8 deficiency type I · C8 deficiency, type I · C81 deficiency · C8A classic complement early component deficiency · C8D1 · classic complement early component deficiency caused by mutation in C8A · complement component 8 deficiency type 1 · complement component 8 deficiency type I · complement component 8 deficiency, type I

Data availability: 14 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 › type I complement component 8 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, complement component C1s deficiency, type II 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

14 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1023205	NM_000562.3(C8A):c.1270C>T (p.Arg424Ter)	C8A	Pathogenic	criteria provided, multiple submitters, no conflicts
1028843	NM_000562.3(C8A):c.630C>A (p.Tyr210Ter)	C8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1396432	NM_000562.3(C8A):c.1492C>T (p.Arg498Ter)	C8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2961734	NM_000562.3(C8A):c.1152T>A (p.Tyr384Ter)	C8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29660	NM_000562.3(C8A):c.171+1G>T	C8A	Likely pathogenic	criteria provided, single submitter
789429	NM_000562.3(C8A):c.1331G>A (p.Arg444His)	C8A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1434860	NM_000562.3(C8A):c.1321A>G (p.Ile441Val)	C8A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1982176	NM_000562.3(C8A):c.155C>T (p.Pro52Leu)	C8A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2103615	NM_000562.3(C8A):c.170A>C (p.Lys57Thr)	C8A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3586017	NM_000562.3(C8A):c.61C>A (p.Gln21Lys)	C8A	Uncertain significance	criteria provided, single submitter
626068	NM_000562.3(C8A):c.1589A>T (p.Gln530Leu)	C8A	Uncertain significance	criteria provided, single submitter
1164179	NM_000562.3(C8A):c.107C>A (p.Ala36Glu)	C8A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
17039	NM_000562.3(C8A):c.277C>A (p.Gln93Lys)	C8A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
791416	NM_000562.3(C8A):c.606T>C (p.Asp202=)	C8A	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
C8A	Strong	Autosomal recessive	type I complement component 8 deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
C8A	Orphanet:169150	Immunodeficiency due to a late component of complement deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C8A	HGNC:1352	ENSG00000157131	P07357	Complement component C8 alpha chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
C8A	Complement component C8 alpha 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: 1 · 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	1	268.0×	0.004

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C8A	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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C8A	46	tissue_specific	marker	right lobe of liver, liver, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C8A	905

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C8A	P07357	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	1427.5×	0.001	C8A
Regulation of Complement cascade	1	233.1×	0.004	C8A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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	1	1296.3×	0.003	C8A
complement activation, alternative pathway	1	991.3×	0.003	C8A
complement activation	1	624.1×	0.003	C8A
complement activation, classical pathway	1	543.6×	0.003	C8A
positive regulation of immune response	1	481.5×	0.003	C8A
killing of cells of another organism	1	271.8×	0.005	C8A
transmembrane transport	1	168.5×	0.007	C8A
immune response	1	47.1×	0.021	C8A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
C8A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	C8A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
C8A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.