Is C8B p.Gln91Ter (c.271C>T) pathogenic?

C8B p.Gln91Ter (c.271C>T) is classified Pathogenic/Likely pathogenic in C8B (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-10). Ultra-rare (popmax 0.0442%, nfe); Associated with C8B-related disorders.

What condition is associated with C8B p.Gln91Ter (c.271C>T)?

C8B p.Gln91Ter (c.271C>T) is associated with C8B-related disorders, complement component 6 deficiency, type II complement component 8 deficiency (ClinVar).

How common is C8B p.Gln91Ter (c.271C>T) in the general population?

C8B p.Gln91Ter (c.271C>T) is ultra-rare (popmax 0.0442%, nfe) (gnomAD).

C8B p.Gln91Ter

c.271C>T · rs146187042 · VCV35594

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0442%, nfe)

Conditions

C8B-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 12
Splicing
SpliceAI	Δ0.42	acceptor loss, 16 bp away · masked 0 · deltas
Pangolin	Δ0.34	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.5	GERP -0.71, phastCons 1
Overall
CADD	36.0	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 0.0442% European (non-Finnish) · 521/1,179,998 alleles

Filtering AF 0.041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0398%

Overall 0.0338% 545/1,613,994 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0442%	2,265
Remaining individualsnot grpmax-eligible	0.0224%	4,463
African / African-American	0.00935%	10,701
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
Admixed American	0.00167%	60,002

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.Gln91Ter
Coding: c.271C>T
MANE Select: NM_000066
dbSNP: rs146187042
Type: single nucleotide variant
Location: chr1:56956889 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 91: a disulfide bond; a UniProt-annotated variant site (in c8d2); a β-strand; the tsp type-1 1 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.Arg284Ter Pathogenic ★★ same condition
C8B p.Arg428Ter Pathogenic ★★ same condition
C8B p.Cys508Ter 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
C8B p.Arg323Trp 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-gln91ter (accessed [today's date]).

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