Is C1R p.Pro216Ala (c.646C>G) pathogenic?

C1R p.Pro216Ala (c.646C>G) is classified Uncertain significance in C1R (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-15). AlphaMissense: likely benign (0.0657); Very rare (popmax 0.00338%, afr); Associated with Ehlers-Danlos syndrome, periodontal type 1.

What condition is associated with C1R p.Pro216Ala (c.646C>G)?

C1R p.Pro216Ala (c.646C>G) is associated with Ehlers-Danlos syndrome, periodontal type 1 (ClinVar).

How common is C1R p.Pro216Ala (c.646C>G) in the general population?

C1R p.Pro216Ala (c.646C>G) is very rare (popmax 0.00338%, afr) (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.Pro216Ala (c.646C>G)?

AlphaMissense predicts likely benign (score 0.0657) — an in-silico prediction, not a clinical call.

C1R p.Pro216Ala

c.646C>G · rs367700816 · VCV1065580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00338%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, periodontal type 1

Computational evidence

Protein change
AlphaMissense	0.0657	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.43	GERP -1.8, phastCons 0.014
Regional constraint	o/e 1.39	unconstrained · MANE · 10 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	0.267	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00338% African / African-American · 2/59,144 alleles

Filtering AF 0.000561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.00115% 9/780,448 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00338%	29,572
Remaining individualsnot grpmax-eligible	0.00284%	35,154
South Asian	0.00268%	37,309
Admixed American	0.0017%	58,974
European (non-Finnish)	0.000718%	139,280

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: C1R
Protein: p.Pro216Ala
Coding: c.646C>G
MANE Select: NM_001733
dbSNP: rs367700816
Type: single nucleotide variant
Location: chr12:7089415 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 87.33 · 12 PDB
Residue 216: a disulfide bond; the cub 2 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

For Periodontal Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

C1R p.Pro216Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
C1R p.Pro216Arg Likely benign ★★ ⚠ 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

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-pro216ala (accessed [today's date]).

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