Is C8B p.Cys508Ter (c.1524C>A) pathogenic?

C8B p.Cys508Ter (c.1524C>A) is classified Pathogenic/Likely pathogenic in C8B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-08). Very rare (popmax 0.000763%, nfe); Associated with C8B-related disorder.

What condition is associated with C8B p.Cys508Ter (c.1524C>A)?

C8B p.Cys508Ter (c.1524C>A) is associated with C8B-related disorder (ClinVar).

How common is C8B p.Cys508Ter (c.1524C>A) in the general population?

C8B p.Cys508Ter (c.1524C>A) is very rare (popmax 0.000763%, nfe) (gnomAD).

C8B p.Cys508Ter

c.1524C>A · rs1176902020 · VCV1452716

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

C8B-related disorder

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 10 of 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.59, phastCons 1
Overall
CADD	35.0	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 0.000763% European (non-Finnish) · 9/1,179,666 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,613,598 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)grpmax	0.000763%	131,074

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys508Ter
Coding: c.1524C>A
MANE Select: NM_000066
dbSNP: rs1176902020
Type: single nucleotide variant
Location: chr1:56933363 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 508: the egf-like domain; a disulfide bond; a UniProt-annotated variant site (in c8d2); an α-helix

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

Disease context

C8B-related disorder

Similar variants

C8B p.Arg428Ter Pathogenic ★★ same condition
C8B p.Gln91Ter Pathogenic/Likely pathogenic ★★ same condition
C8B p.Arg121Ter Conflicting classifications of pathogenicity ★ same condition
C8B p.Ala461= Likely benign same condition
C8B p.Arg284Ter Pathogenic ★★ same type
C8B p.Trp9Ter Pathogenic ★★ same type
C8B p.Ala21Thr Uncertain significance ★★ ⚠ same type
C8B p.Ala446Val Uncertain significance ★★ ⚠ same type

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-cys508ter (accessed [today's date]).

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