Is PROC p.Arg57Trp (c.169C>T) pathogenic?

PROC p.Arg57Trp (c.169C>T) is classified Pathogenic/Likely pathogenic in PROC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.3331); Very rare (popmax 0.00223%, eas); Associated with thrombophilia due to protein C deficiency, autosomal recessive.

What condition is associated with PROC p.Arg57Trp (c.169C>T)?

PROC p.Arg57Trp (c.169C>T) is associated with thrombophilia due to protein C deficiency, autosomal recessive, thrombophilia due to protein C deficiency, autosomal dominant, hereditary thrombophilia due to congenital protein C deficiency (ClinVar).

How common is PROC p.Arg57Trp (c.169C>T) in the general population?

PROC p.Arg57Trp (c.169C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PROC p.Arg57Trp (c.169C>T)?

AlphaMissense predicts likely benign (score 0.3331) — an in-silico prediction, not a clinical call.

PROC p.Arg57Trp

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.169C>T · rs757583846 · VCV188230

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3331 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein C deficiency, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.3331	likely benign ⚠ discordant with ClinVar
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -13.68	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	phastCons 0.95
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	23.4	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 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00167% 27/1,613,774 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
European (non-Finnish)	0.00212%	47,198
South Asian	0.0011%	91,086

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.Arg57Trp
Coding: c.169C>T
MANE Select: NM_000312
dbSNP: rs757583846
Type: single nucleotide variant
Location: chr2:127421381 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 57: an α-helix; a UniProt-annotated variant site (in yonago; defective anticoagulant activity); a UniProt-annotated variant site (in patients with proc deficiency); a UniProt-annotated variant site (in thph3); the gla domain

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

Disease context

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

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

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.Arg57Gln 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
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-arg57trp (accessed [today's date]).

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