Is C8B p.Glu66fs (c.197del) pathogenic?

C8B p.Glu66fs (c.197del) is classified Pathogenic in C8B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-21). Very rare (popmax 0.000763%, nfe).

How common is C8B p.Glu66fs (c.197del) in the general population?

C8B p.Glu66fs (c.197del) is very rare (popmax 0.000763%, nfe) (gnomAD).

C8B p.Glu66fs

c.197del · rs1557743907 · VCV2697996

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.4	GERP -4.3

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) · 9/1,180,006 alleles

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

Overall 0.000616% 9/1,461,860 alleles · very rare

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.Glu66fs
Coding: c.197del
MANE Select: NM_000066
dbSNP: rs1557743907
Type: Deletion
Location: chr1:56960072 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 66: a disulfide bond; the tsp type-1 1 domain

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

Similar variants

C8B p.Glu66Asp Uncertain significance ★ ⚠ same residue
C8B p.Phe47fs Pathogenic/Likely pathogenic ★★ same type
C8B p.Asn113fs Pathogenic ★ same type
C8B p.Asn184fs Pathogenic ★ same type
C8B p.Cys24fs Pathogenic ★ same type
C8B p.Leu18fs Pathogenic ★ same type
C8B p.Leu372fs Pathogenic ★ same type
C8B p.Met248fs Pathogenic ★ 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-glu66fs (accessed [today's date]).

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