Is C8B p.Arg428Ter (c.1282C>T) pathogenic?

C8B p.Arg428Ter (c.1282C>T) is classified Pathogenic in C8B (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-04-21). Rare (popmax 0.297%, mid); Associated with C8B-related disorders.

What condition is associated with C8B p.Arg428Ter (c.1282C>T)?

C8B p.Arg428Ter (c.1282C>T) is associated with C8B-related disorders, complement component 6 deficiency, type II complement component 8 deficiency (ClinVar).

How common is C8B p.Arg428Ter (c.1282C>T) in the general population?

C8B p.Arg428Ter (c.1282C>T) is rare (popmax 0.297%, mid) (gnomAD).

C8B p.Arg428Ter

c.1282C>T · rs41286844 · VCV17038

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 19 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.297%, mid)

Conditions

C8B-related disorders

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 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.15, phastCons 1
Overall
CADD	40.0	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 0.297% Middle Eastern · 18/6,062 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.132% 2,134/1,613,758 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.297%	337
European (non-Finnish)	0.159%	630
Remaining individualsnot grpmax-eligible	0.128%	781
Admixed American	0.0767%	1,304
Finnishnot grpmax-eligible	0.0687%	1,455
South Asian	0.0406%	2,461
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,691
African / African-American	0.0321%	3,120
East Asian	0.00446%	22,409

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: C8B
Protein: p.Arg428Ter
Coding: c.1282C>T
MANE Select: NM_000066
dbSNP: rs41286844
Type: single nucleotide variant
Location: chr1:56940965 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 428: a UniProt-annotated variant site (in c8d2); the macpf domain

Full C8B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

C8B-related disorders

Also linked: complement component 6 deficiency type II complement component 8 deficiency

Similar variants

C8B p.Arg428Gln Uncertain significance ★★ ⚠ same residue
C8B p.Arg284Ter Pathogenic ★★ same condition
C8B p.Cys508Ter Pathogenic/Likely pathogenic ★★ same condition
C8B p.Gln91Ter Pathogenic/Likely pathogenic ★★ same condition
C8B p.Trp9Ter Pathogenic ★★ same condition
C8B p.Ala461Ser Uncertain significance ★★ ⚠ same condition
C8B p.Ala480Thr Uncertain significance ★★ ⚠ same condition
C8B p.Arg136His Uncertain significance ★★ ⚠ 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/c8b-p-arg428ter (accessed [today's date]).

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