Is C1S p.Cys294Arg (c.880T>C) pathogenic?

C1S p.Cys294Arg (c.880T>C) is classified Pathogenic in C1S (ClinVar, Single submitter, 3 submitters; last evaluated 2016-08-23). AlphaMissense: likely pathogenic (0.9534); Very rare (popmax 0.00223%, eas); Associated with Ehlers-Danlos syndrome, periodontal type 1.

What condition is associated with C1S p.Cys294Arg (c.880T>C)?

C1S p.Cys294Arg (c.880T>C) is associated with Ehlers-Danlos syndrome, periodontal type 1, Ehlers-Danlos syndrome, periodontal type 2 (ClinVar).

How common is C1S p.Cys294Arg (c.880T>C) in the general population?

C1S p.Cys294Arg (c.880T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Periodontal Ehlers-Danlos syndrome inherited?

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

What do computational predictors say about C1S p.Cys294Arg (c.880T>C)?

AlphaMissense predicts likely pathogenic (score 0.9534) — an in-silico prediction, not a clinical call.

C1S p.Cys294Arg

c.880T>C · rs886040975 · VCV267349

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, periodontal type 1

Computational evidence

Protein change
AlphaMissense	0.9534	likely pathogenic ✓ concordant with ClinVar · top 6% in C1S
REVEL	0.846	moderately pathogenic-leaning
SaProt	LLR -12.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 4,638 bp · p 0.66 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,836 alleles

Overall 6.88e-05% 1/1,452,478 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.Cys294Arg
Coding: c.880T>C
MANE Select: NM_001734
dbSNP: rs886040975
Type: single nucleotide variant
Location: chr12:7066526 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 294: a disulfide bond; a UniProt-annotated variant site (in edspd2); the sushi 1 domain

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

Disease context

Ehlers-Danlos syndrome, periodontal type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, periodontal type 2

For Periodontal Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

C1S p.Arg523Ter Pathogenic ★★ 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
C1S p.Lys669Asn 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-cys294arg (accessed [today's date]).

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