Is C8A p.Arg424Ter (c.1270C>T) pathogenic?

C8A p.Arg424Ter (c.1270C>T) is classified Pathogenic in C8A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). Ultra-rare (popmax 0.0294%, afr); Associated with type I complement component 8 deficiency.

What condition is associated with C8A p.Arg424Ter (c.1270C>T)?

C8A p.Arg424Ter (c.1270C>T) is associated with type I complement component 8 deficiency (ClinVar).

How common is C8A p.Arg424Ter (c.1270C>T) in the general population?

C8A p.Arg424Ter (c.1270C>T) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

C8A p.Arg424Ter

Q: How is Immunodeficiency due to a late component of complement deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1270C>T · rs140856114 · VCV1023205

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Conditions

type I complement component 8 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.24	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.55	GERP 0.51, phastCons 0.009
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0294% African / African-American · 22/74,902 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00223% 36/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,405
Remaining individualsnot grpmax-eligible	0.0032%	31,242
South Asian	0.0022%	45,538
European (non-Finnish)	0.000847%	118,003

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: C8A
Protein: p.Arg424Ter
Coding: c.1270C>T
MANE Select: NM_000562
dbSNP: rs140856114
Type: single nucleotide variant
Location: chr1:56908003 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 424: a UniProt-annotated variant site (in c8d1); the macpf domain

Full C8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

type I complement component 8 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a late component of complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C8A p.Arg424= Likely benign ★ same residue
C8A p.Arg498Ter Pathogenic/Likely pathogenic ★★ same condition
C8A p.Tyr210Ter Pathogenic/Likely pathogenic ★★ same condition
C8A p.Tyr384Ter Pathogenic/Likely pathogenic ★★ same condition
C8A p.Ile441Val Uncertain significance ★★ ⚠ same condition
C8A p.Lys57Thr Uncertain significance ★★ ⚠ same condition
C8A p.Pro52Leu Uncertain significance ★★ ⚠ same condition
C8A p.Ala36Glu Benign/Likely benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/c8a-p-arg424ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown