Is PROC p.Trp225Arg (c.673T>C) pathogenic?

PROC p.Trp225Arg (c.673T>C) is classified Likely pathogenic in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-21). AlphaMissense: likely pathogenic (0.9959); Very rare (popmax 0.000339%, nfe); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Trp225Arg (c.673T>C)?

PROC p.Trp225Arg (c.673T>C) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Trp225Arg (c.673T>C) in the general population?

PROC p.Trp225Arg (c.673T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about PROC p.Trp225Arg (c.673T>C)?

AlphaMissense predicts likely pathogenic (score 0.9959) — an in-silico prediction, not a clinical call.

PROC p.Trp225Arg

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.673T>C · rs1277271891 · VCV1330274

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.9959	likely pathogenic ✓ concordant with ClinVar · top 1% in PROC
REVEL	0.879	moderately pathogenic-leaning
SaProt	LLR -13.79	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	28.7	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 0.000339% European (non-Finnish) · 4/1,180,026 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,932 alleles · very rare exomes 4/1,461,668 · genomes 0/152,264 · joint denominator

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.Trp225Arg
Coding: c.673T>C
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

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.Trp225Ter Pathogenic ★ same residue
PROC p.Trp225Gly 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
PROC p.Arg220Trp 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-trp225arg (accessed [today's date]).

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