Is C1S p.Arg686fs (c.2056dup) pathogenic?

C1S p.Arg686fs (c.2056dup) is classified Uncertain significance in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-08). Very rare (popmax 0.00223%, eas).

How common is C1S p.Arg686fs (c.2056dup) in the general population?

C1S p.Arg686fs (c.2056dup) is very rare (popmax 0.00223%, eas) (gnomAD).

C1S p.Arg686fs

c.2056dup · rs1565625392 · VCV1392152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 -0.36	GERP -3.4
Overall
CADD	21.2	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 0.00223% East Asian · 1/44,870 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,612,872 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,870
Remaining individualsnot grpmax-eligible	0.0016%	62,454
European (non-Finnish)	0.00017%	589,929

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.Arg686fs
Coding: c.2056dup
MANE Select: NM_001734
dbSNP: rs1565625392
Type: Duplication
Location: chr12:7070634 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB

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

Similar variants

C1S p.Arg686His Uncertain significance ★★ ⚠ same residue
C1S p.Arg686Leu Uncertain significance ★★ ⚠ same residue
C1S p.Arg686Cys Uncertain significance ★ ⚠ same residue
C1S p.Asp178fs Pathogenic ★ same type
C1S p.Asp269fs Pathogenic ★ same type
C1S p.Leu82fs Pathogenic ★ same type
C1S p.Asn642fs Uncertain significance ★ same type
C1S p.Asp673delinsGlyTer Uncertain significance ★ 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-arg686fs (accessed [today's date]).

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