Is C8B p.Arg121Ter (c.361C>T) pathogenic?

C8B p.Arg121Ter (c.361C>T) is classified Conflicting classifications of pathogenicity in C8B (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-03-13). Ultra-rare (popmax 0.099%, mid); Associated with C8B-related disorders.

What condition is associated with C8B p.Arg121Ter (c.361C>T)?

C8B p.Arg121Ter (c.361C>T) is associated with C8B-related disorders, type II complement component 8 deficiency (ClinVar).

How common is C8B p.Arg121Ter (c.361C>T) in the general population?

C8B p.Arg121Ter (c.361C>T) is ultra-rare (popmax 0.099%, mid) (gnomAD).

C8B p.Arg121Ter

c.361C>T · rs150022116 · VCV35593

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, 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 3 of 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.4, phastCons 1
Overall
CADD	38.0	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 0.099% Middle Eastern · 6/6,060 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.00929% 150/1,613,906 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,691
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	0.01%	10,000
Admixed American	0.005%	20,001
South Asian	0.00439%	22,767
East Asian	0.00223%	44,836

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.Arg121Ter
Coding: c.361C>T
MANE Select: NM_000066
dbSNP: rs150022116
Type: single nucleotide variant
Location: chr1:56956799 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 121: a UniProt-annotated variant site (in c8d2); the ldl-receptor class a domain

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

Disease context

C8B-related disorders

Also linked: type II complement component 8 deficiency

Similar variants

C8B p.Arg121= Likely benign ★ same residue
C8B p.Arg284Ter Pathogenic ★★ same condition
C8B p.Arg428Ter 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

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-arg121ter (accessed [today's date]).

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