Is PROC p.Arg189Gly (c.565C>G) pathogenic?

PROC p.Arg189Gly (c.565C>G) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-06). AlphaMissense: likely benign (0.0955); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PROC p.Arg189Gly (c.565C>G)?

PROC p.Arg189Gly (c.565C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PROC p.Arg189Gly (c.565C>G) in the general population?

PROC p.Arg189Gly (c.565C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROC p.Arg189Gly (c.565C>G)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

PROC p.Arg189Gly

c.565C>G · VCV3425580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0955	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.39	acceptor loss, 29 bp away · masked 0 · deltas
Pangolin	Δ0.24	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.23
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	10.54	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.Arg189Gly
Coding: c.565C>G
MANE Select: NM_000312
Type: single nucleotide variant
Location: chr2:127426114 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 189: a disulfide bond; a UniProt-annotated variant site (in patients with proc deficiency; la jolla-3)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROC p.Arg189Gln Uncertain significance ★ ⚠ same residue
PROC p.Arg189Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
PROC p.Arg189= Likely benign ★ same residue
PROC p.Asp401Asn Pathogenic/Likely pathogenic ★★ same condition
PROC p.Val339Met Pathogenic ★★ same condition
PROC p.Trp414Arg Uncertain significance ★★ ⚠ same condition
PROC p.Asn384Ser Uncertain significance ★ ⚠ same condition
PROC p.Asn431Ser 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/proc-p-arg189gly (accessed [today's date]).

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