Is C1S p.Arg523Ter (c.1567C>T) pathogenic?

C1S p.Arg523Ter (c.1567C>T) is classified Pathogenic in C1S (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-06). Very rare (popmax 0.0011%, sas); Associated with Ehlers-Danlos syndrome, periodontal type 2.

What condition is associated with C1S p.Arg523Ter (c.1567C>T)?

C1S p.Arg523Ter (c.1567C>T) is associated with Ehlers-Danlos syndrome, periodontal type 2, complement component C1s deficiency (ClinVar).

How common is C1S p.Arg523Ter (c.1567C>T) in the general population?

C1S p.Arg523Ter (c.1567C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Periodontal Ehlers-Danlos syndrome inherited?

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

C1S p.Arg523Ter

c.1567C>T · rs781856506 · VCV2137294

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Ehlers-Danlos syndrome, periodontal type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	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 · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.57	GERP -1.7, phastCons 0.071
Overall
CADD	35.0	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 0.0011% South Asian · 1/91,082 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000752% 11/1,461,882 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	0.000847%	118,003

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.Arg523Ter
Coding: c.1567C>T
MANE Select: NM_001734
dbSNP: rs781856506
Type: single nucleotide variant
Location: chr12:7070151 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 523: a disulfide bond; the peptidase s1 domain

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

Disease context

Ehlers-Danlos syndrome, periodontal type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: complement component C1s deficiency

For Periodontal Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

C1S p.Arg523Leu Likely benign ⚠ same residue
C1S p.Arg245Trp Uncertain significance ★★ ⚠ same condition
C1S p.Arg331Cys Uncertain significance ★★ ⚠ same condition
C1S p.Arg534Trp Uncertain significance ★★ ⚠ same condition
C1S p.Arg572Gln Uncertain significance ★★ ⚠ same condition
C1S p.Asn116Ser Uncertain significance ★★ ⚠ same condition
C1S p.Gly172Arg Uncertain significance ★★ ⚠ same condition
C1S p.Gly243Arg 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-arg523ter (accessed [today's date]).

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