Is C9 p.Cys142fs (c.423dup) pathogenic?

C9 p.Cys142fs (c.423dup) is classified Pathogenic in C9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-24). Very rare (popmax 0.000932%, nfe).

How common is C9 p.Cys142fs (c.423dup) in the general population?

C9 p.Cys142fs (c.423dup) is very rare (popmax 0.000932%, nfe) (gnomAD).

C9 p.Cys142fs

c.423dup · rs1041610302 · VCV1924368

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000932%, 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 4 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Overall
CADD	27.6	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 0.000932% European (non-Finnish) · 11/1,180,008 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000743% 12/1,614,032 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)grpmax	0.000932%	107,273

Remaining individuals 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: C9
Protein: p.Cys142fs
Coding: c.423dup
MANE Select: NM_001737
dbSNP: rs1041610302
Type: Duplication
Location: chr5:39341198 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 142: the macpf domain; a disulfide bond; a turn

Full C9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C9 p.Glu98Ter Pathogenic ★ same type
C9 p.Ile359fs Pathogenic ★ same type
C9 p.Leu489fs Conflicting classifications of pathogenicity ★ same type
C9 c.476+11dup Benign ★ same type
C9 c.616-19_616-17dup Likely benign ★ 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/c9-p-cys142fs (accessed [today's date]).

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