Is C1R p.Cys358Phe (c.1073G>T) pathogenic?

C1R p.Cys358Phe (c.1073G>T) is classified Pathogenic in C1R (ClinVar, Single submitter, 3 submitters; last evaluated 2016-08-23). AlphaMissense: likely pathogenic (0.9818); Absent from gnomAD v4.1; Associated with Ehlers-Danlos syndrome, periodontal type 1.

What condition is associated with C1R p.Cys358Phe (c.1073G>T)?

C1R p.Cys358Phe (c.1073G>T) is associated with Ehlers-Danlos syndrome, periodontal type 1, Ehlers-Danlos syndrome, periodontal type 2 (ClinVar).

How common is C1R p.Cys358Phe (c.1073G>T) in the general population?

C1R p.Cys358Phe (c.1073G>T) is absent from gnomAD v4.1 (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 C1R p.Cys358Phe (c.1073G>T)?

AlphaMissense predicts likely pathogenic (score 0.9818) — an in-silico prediction, not a clinical call.

C1R p.Cys358Phe

c.1073G>T · rs1057518645 · VCV267351

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9818 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Conditions

Ehlers-Danlos syndrome, periodontal type 1

Computational evidence

Protein change
AlphaMissense	0.9818	likely pathogenic ✓ concordant with ClinVar · top 5% in C1R
SaProt	LLR -16.34	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 10 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	25.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C1R
Protein: p.Cys358Phe
Coding: c.1073G>T
MANE Select: NM_001733
dbSNP: rs1057518645
Type: single nucleotide variant
Location: chr12:7086423 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 87.33 · 12 PDB
Residue 358: a β-strand; a disulfide bond; a UniProt-annotated variant site (in edspd1); the sushi 1 domain

Full C1R 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

C1R p.Cys358Tyr Likely pathogenic ★ same residue
C1R p.Arg301Pro Pathogenic ★★ ⚠ same condition
C1R p.Asp290Gly Pathogenic/Likely pathogenic ★★ same condition
C1R p.Cys338Arg Pathogenic ★★ same condition
C1R p.Cys371Trp Pathogenic ★★ same condition
C1R p.Gly297Asp Pathogenic/Likely pathogenic ★★ same condition
C1R c.231+6G>A Benign/Likely benign ★★ same condition
C1R p.Cys309Arg Likely pathogenic ★ 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/c1r-p-cys358phe (accessed [today's date]).

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