Is PROC p.Arg189Trp (c.565C>T) pathogenic?

PROC p.Arg189Trp (c.565C>T) is classified Conflicting classifications of pathogenicity in PROC (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2025-09-24). AlphaMissense: likely benign (0.0952); Rare (popmax 0.448%, eas); Associated with PROC-related disorder.

What condition is associated with PROC p.Arg189Trp (c.565C>T)?

PROC p.Arg189Trp (c.565C>T) is associated with PROC-related disorder, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Arg189Trp (c.565C>T) in the general population?

PROC p.Arg189Trp (c.565C>T) is rare (popmax 0.448%, eas) (gnomAD).

What do computational predictors say about PROC p.Arg189Trp (c.565C>T)?

AlphaMissense predicts likely benign (score 0.0952) — an in-silico prediction, not a clinical call.

PROC p.Arg189Trp

c.565C>T · rs146922325 · VCV161342

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0952 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.448%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PROC-related disorder

Computational evidence

Protein change
AlphaMissense	0.0952	likely benign
REVEL	0.585	indeterminate
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.39 · evaluated, not missing
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	13.64	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 0.448% East Asian · 201/44,878 alleles

Filtering AF 0.397% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.378%

Overall 0.0232% 374/1,614,004 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.448%	223
Remaining individualsnot grpmax-eligible	0.088%	1,136
South Asian	0.0736%	1,360
African / African-American	0.0133%	7,500
Admixed American	0.005%	20,001
European (non-Finnish)	0.00322%	31,053

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: PROC
Protein: p.Arg189Trp
Coding: c.565C>T
MANE Select: NM_000312
dbSNP: rs146922325
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 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

PROC-related disorder

Also linked: thrombophilia due to protein C deficiency, autosomal dominant

Similar variants

PROC p.Arg189Gln Uncertain significance ★ ⚠ same residue
PROC p.Arg189= Likely benign ★ same residue
PROC p.Arg189Gly Uncertain significance ★ ⚠ 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.Arg220Gln 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-arg189trp (accessed [today's date]).

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