C8A

Chr 1AR

complement C8 alpha chain

NCBI Gene: 731 ENSG00000157131 UniProt: P07357 OMIM: 120950

The C8A protein is the alpha subunit of complement component C8, which forms part of the membrane attack complex that creates pores in bacterial membranes leading to cell lysis and pathogen clearance. Mutations cause complement C8 deficiency type I, inherited in an autosomal recessive pattern, which results in increased susceptibility to recurrent Neisseria infections. This gene shows minimal constraint against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

C8 is a component of the complement system and contains three polypeptides, alpha, beta and gamma. This gene encodes the alpha subunit of C8. C8 participates in the formation of the membrane attack complex (MAC). The MAC assembles on bacterial membranes to form a pore, permitting disruption of bacterial membrane organization. Mutations in this gene cause complement C8 alpha-gamma deficiency. [provided by RefSeq, Nov 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.181 OMIM phenotype

Clinical Summary— C8A

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.000

Z-score 0.75

OE 0.85 (0.63–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.07Z-score

OE missense 1.17 (1.07–1.27)

372 obs / 318.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.85 (0.63–1.18)

0≤0.351.4

Missense OE?1.17 (1.07–1.27)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 26 / 30.5Missense obs/exp: 372 / 318.1Syn Z: -1.10

This gene — mechanism propensity

0.6260th %ile

GOF

0.5856th %ile

LOF

0.2969th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.