Is PROC p.Gly239Arg (c.715G>A) pathogenic?

PROC p.Gly239Arg (c.715G>A) is classified Likely pathogenic in PROC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-13). AlphaMissense: likely pathogenic (0.9315); Very rare (popmax 0.00133%, afr); Associated with Deep venous thrombosis.

What condition is associated with PROC p.Gly239Arg (c.715G>A)?

PROC p.Gly239Arg (c.715G>A) is associated with Deep venous thrombosis, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Gly239Arg (c.715G>A) in the general population?

PROC p.Gly239Arg (c.715G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PROC p.Gly239Arg (c.715G>A)?

AlphaMissense predicts likely pathogenic (score 0.9315) — an in-silico prediction, not a clinical call.

PROC p.Gly239Arg

c.715G>A · rs777486993 · VCV627365

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Deep venous thrombosis

Computational evidence

Protein change
AlphaMissense	0.9315	likely pathogenic ✓ concordant with ClinVar
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -14.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	29.4	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 0.00133% African / African-American · 1/75,060 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,844 alleles · very rare exomes 4/1,461,520 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,060
South Asian	0.0011%	91,074
European (non-Finnish)	0.000169%	589,984

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.Gly239Arg
Coding: c.715G>A
MANE Select: NM_000312
dbSNP: rs777486993
Type: single nucleotide variant
Location: chr2:127427141 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 239: a β-strand; 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

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

Similar variants

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
PROC p.Arg272Cys 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-gly239arg (accessed [today's date]).

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