Is C9 p.Met293fs (c.877del) pathogenic?

C9 p.Met293fs (c.877del) is classified Pathogenic/Likely pathogenic in C9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-30). Ultra-rare (popmax 0.03%, amr); Associated with C9-related disorder.

What condition is associated with C9 p.Met293fs (c.877del)?

C9 p.Met293fs (c.877del) is associated with C9-related disorder (ClinVar).

How common is C9 p.Met293fs (c.877del) in the general population?

C9 p.Met293fs (c.877del) is ultra-rare (popmax 0.03%, amr) (gnomAD).

C9 p.Met293fs

c.877del · rs777158966 · VCV2178973

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Conditions

C9-related disorder

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 7 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	GERP -3.3, phastCons 0.001
Overall
CADD	17.47	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 0.03% Admixed American · 18/59,978 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00211% 34/1,612,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,332
Remaining individualsnot grpmax-eligible	0.0032%	31,231
East Asian	0.00223%	44,862
African / African-American	0.00133%	74,994
European (non-Finnish)	0.00102%	98,255

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.Met293fs
Coding: c.877del
MANE Select: NM_001737
dbSNP: rs777158966
Type: Deletion
Location: chr5:39311371 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 293: the macpf domain; a β-strand

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

Disease context

C9-related disorder

Similar variants

C9 p.Asp403fs Pathogenic/Likely pathogenic ★★ same condition
C9 p.Tyr193fs Pathogenic/Likely pathogenic ★★ same condition
C9 p.Met293Val Uncertain significance ★★ ⚠ same residue
C9 p.Met293Ile Uncertain significance ★ ⚠ same residue
C9 c.871-2A>G Likely pathogenic ★★ same condition
C9 p.Arg116Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg194Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg86Ter Pathogenic/Likely pathogenic ★★ 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/c9-p-met293fs (accessed [today's date]).

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