Is C1S p.Arg481fs (c.1441_1442del) pathogenic?

C1S p.Arg481fs (c.14411442del) is classified Pathogenic in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-19). Very rare (popmax 0.00267%, afr).

How common is C1S p.Arg481fs (c.1441_1442del) in the general population?

C1S p.Arg481fs (c.1441_1442del) is very rare (popmax 0.00267%, afr) (gnomAD).

C1S p.Arg481fs

c.1441_1442del · rs782751698 · VCV1384223

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (12 of 12) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.9	GERP -3.6
Overall
CADD	17.92	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 0.00267% African / African-American · 2/74,898 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,152 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.Arg481fs
Coding: c.1441_1442del
MANE Select: NM_001734
dbSNP: rs782751698
Type: Deletion
Location: chr12:7070025 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 481: a disulfide bond; the peptidase s1 domain

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

Similar variants

C1S p.Arg481Gly Uncertain significance ★★ ⚠ same residue
C1S p.Arg481= Likely benign ★ same residue
C1S p.Ser115fs Pathogenic ★★ same type
C1S c.518-13_518-6del Benign/Likely benign ★★ same type
C1S c.6-10_6-9del Likely benign ★★ same type
C1S p.Asn233fs Pathogenic ★ same type
C1S p.Asn27fs Pathogenic ★ same type
C1S p.Asn344fs 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/c1s-p-arg481fs (accessed [today's date]).

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