Is C1S p.Ser115fs (c.343del) pathogenic?

C1S p.Ser115fs (c.343del) is classified Pathogenic in C1S (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-19). Very rare (popmax 8.47e-05%, nfe); Associated with complement component C1s deficiency.

What condition is associated with C1S p.Ser115fs (c.343del)?

C1S p.Ser115fs (c.343del) is associated with complement component C1s deficiency (ClinVar).

How common is C1S p.Ser115fs (c.343del) in the general population?

C1S p.Ser115fs (c.343del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

C1S p.Ser115fs

Q: How is Immunodeficiency due to a classical component pathway complement deficiency inherited?

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

c.343del · VCV3336211

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

complement component C1s 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 4 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.79	GERP -2.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,844 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: C1S
Protein: p.Ser115fs
Coding: c.343del
MANE Select: NM_001734
Type: Deletion
Location: chr12:7063016 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 115: the cub 1 domain

Full C1S gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component C1s deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a classical component pathway complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C1S p.Gln493fs Pathogenic ★ same condition
C1S p.Ser115Phe Uncertain significance ★ ⚠ same residue
C1S p.Arg437fs Pathogenic/Likely pathogenic ★★ same condition
C1S p.Arg523Ter Pathogenic ★★ same condition
C1S p.Arg245Trp Uncertain significance ★★ ⚠ same condition
C1S p.Arg331Cys Uncertain significance ★★ ⚠ same condition
C1S p.Arg534Trp Uncertain significance ★★ ⚠ same condition
C1S p.Gly172Arg 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/c1s-p-ser115fs (accessed [today's date]).

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