Is PROC p.Trp225Gly (c.673T>G) pathogenic?

PROC p.Trp225Gly (c.673T>G) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-01). AlphaMissense: likely pathogenic (0.9131); Very rare (popmax 8.47e-05%, nfe); Associated with Deep venous thrombosis.

What condition is associated with PROC p.Trp225Gly (c.673T>G)?

PROC p.Trp225Gly (c.673T>G) is associated with Deep venous thrombosis (ClinVar).

How common is PROC p.Trp225Gly (c.673T>G) in the general population?

PROC p.Trp225Gly (c.673T>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PROC p.Trp225Gly (c.673T>G)?

AlphaMissense predicts likely pathogenic (score 0.9131) — an in-silico prediction, not a clinical call.

PROC p.Trp225Gly

c.673T>G · rs1277271891 · VCV627113

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9131 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Deep venous thrombosis

Computational evidence

Protein change
AlphaMissense	0.9131	likely pathogenic
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -13.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,668 alleles · very rare

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.Trp225Gly
Coding: c.673T>G
MANE Select: NM_000312
dbSNP: rs1277271891
Type: single nucleotide variant
Location: chr2:127426222 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 225: the peptidase s1 domain

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

Disease context

Deep venous thrombosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROC p.Trp225Arg Likely pathogenic ★ same residue
PROC p.Trp225Ter Pathogenic ★ same residue
PROC p.Arg42His Likely pathogenic ★★ ⚠ same condition
PROC p.Gly239Arg Likely pathogenic ★★ same condition
PROC p.Phe118Leu Likely pathogenic ★★ same condition
PROC p.Pro321Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Glu191Gln Uncertain significance ★★ ⚠ same condition
PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same type

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-trp225gly (accessed [today's date]).

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