Is C9 p.Ser395fs (c.1184_1185del) pathogenic?

C9 p.Ser395fs (c.11841185del) is classified Pathogenic/Likely pathogenic in C9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-14). Ultra-rare (popmax 0.0165%, mid); Associated with complement component 9 deficiency.

What condition is associated with C9 p.Ser395fs (c.1184_1185del)?

C9 p.Ser395fs (c.1184_1185del) is associated with complement component 9 deficiency, age related macular degeneration 15 (ClinVar).

How common is C9 p.Ser395fs (c.1184_1185del) in the general population?

C9 p.Ser395fs (c.1184_1185del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

C9 p.Ser395fs

Q: How is Immunodeficiency due to a late component of complement deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1184_1185del · rs752437276 · VCV1455046

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

complement component 9 deficiency

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 8 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.69	GERP -3.8
Overall
CADD	19.18	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 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000832%

Overall 0.0013% 21/1,611,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
European (non-Finnish)	0.00161%	61,966
Remaining individualsnot grpmax-eligible	0.0016%	62,384

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.Ser395fs
Coding: c.1184_1185del
MANE Select: NM_001737
dbSNP: rs752437276
Type: Microsatellite
Location: chr5:39308285 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 395: the macpf domain; a disulfide bond

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

Disease context

complement component 9 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 15

For Immunodeficiency due to a late component of complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C9 p.Arg116Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg154Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg194Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Cys54Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Ser240_Leu241insTer Pathogenic/Likely pathogenic ★★ same condition
C9 p.Ser347fs Pathogenic/Likely pathogenic ★★ same condition
C9 p.Tyr193fs Pathogenic/Likely pathogenic ★★ same condition
C9 p.Gly126Arg 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/c9-p-ser395fs (accessed [today's date]).

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