Is PROC p.Arg220Pro (c.659G>C) pathogenic?

PROC p.Arg220Pro (c.659G>C) is classified Uncertain significance in PROC (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-09). AlphaMissense: likely benign (0.1574); Absent from gnomAD v4.1; Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Arg220Pro (c.659G>C)?

PROC p.Arg220Pro (c.659G>C) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Arg220Pro (c.659G>C) in the general population?

PROC p.Arg220Pro (c.659G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROC p.Arg220Pro (c.659G>C)?

AlphaMissense predicts likely benign (score 0.1574) — an in-silico prediction, not a clinical call.

PROC p.Arg220Pro

Q: How is Severe hereditary thrombophilia due to congenital protein C deficiency inherited?

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

c.659G>C · rs121918153 · VCV1684349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1574 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.1574	likely benign
REVEL	0.557	indeterminate
SaProt	LLR -4.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	phastCons 0.65
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	20.8	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

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: PROC
Protein: p.Arg220Pro
Coding: c.659G>C
MANE Select: NM_000312
dbSNP: rs121918153
Type: single nucleotide variant
Location: chr2:127426208 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 220: a disulfide bond; a UniProt-annotated variant site (in patients with proc deficiency); a UniProt-annotated variant site (in thph3; vermont-3); a UniProt-annotated variant site (in thph3); the peptidase s1 domain

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

Disease context

thrombophilia due to protein C deficiency, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe hereditary thrombophilia due to congenital protein C deficiency (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
PROC p.Arg220Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
PROC p.Arg220= Likely benign ★ same residue
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter Pathogenic ★★ same condition
PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg271Trp Pathogenic/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/proc-p-arg220pro (accessed [today's date]).

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