Is C1S p.Arg534Trp (c.1600C>T) pathogenic?

C1S p.Arg534Trp (c.1600C>T) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-05-28). AlphaMissense: likely benign (0.1937); Ultra-rare (popmax 0.0148%, nfe); Associated with Ehlers-Danlos syndrome, periodontal type 2.

What condition is associated with C1S p.Arg534Trp (c.1600C>T)?

C1S p.Arg534Trp (c.1600C>T) is associated with Ehlers-Danlos syndrome, periodontal type 2, complement component C1s deficiency (ClinVar).

How common is C1S p.Arg534Trp (c.1600C>T) in the general population?

C1S p.Arg534Trp (c.1600C>T) is ultra-rare (popmax 0.0148%, nfe) (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.Arg534Trp (c.1600C>T)?

AlphaMissense predicts likely benign (score 0.1937) — an in-silico prediction, not a clinical call.

C1S p.Arg534Trp

c.1600C>T · rs121909582 · VCV17068

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1937 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Ehlers-Danlos syndrome, periodontal type 2

Computational evidence

Protein change
AlphaMissense	0.1937	likely benign
REVEL	0.542	indeterminate
SaProt	LLR -11.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP 0.63, phastCons 0.082
Regional constraint	o/e 0.79	unconstrained · MANE · 3,608 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	26.8	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 0.0148% European (non-Finnish) · 175/1,180,006 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.0118% 190/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0148%	6,743
Admixed American	0.0117%	8,571
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,890
Finnishnot grpmax-eligible	0.00156%	64,030
African / African-American	0.00133%	74,932
South Asian	0.0011%	91,076

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.Arg534Trp
Coding: c.1600C>T
MANE Select: NM_001734
dbSNP: rs121909582
Type: single nucleotide variant
Location: chr12:7070184 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 534: a β-strand; 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.Arg534Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
C1S p.Arg523Ter Pathogenic ★★ same condition
C1S p.Arg245Trp Uncertain significance ★★ ⚠ same condition
C1S p.Arg331Cys 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-arg534trp (accessed [today's date]).

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