Is PROC p.Arg42His (c.125G>A) pathogenic?

PROC p.Arg42His (c.125G>A) is classified Likely pathogenic in PROC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-14). AlphaMissense: likely benign (0.3198); Very rare (popmax 0.000424%, nfe); Associated with Deep venous thrombosis.

What condition is associated with PROC p.Arg42His (c.125G>A)?

PROC p.Arg42His (c.125G>A) is associated with Deep venous thrombosis, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Arg42His (c.125G>A) in the general population?

PROC p.Arg42His (c.125G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about PROC p.Arg42His (c.125G>A)?

AlphaMissense predicts likely benign (score 0.3198) — an in-silico prediction, not a clinical call.

PROC p.Arg42His

c.125G>A · rs369504169 · VCV161333

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3198 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Deep venous thrombosis

Computational evidence

Protein change
AlphaMissense	0.3198	likely benign ⚠ discordant with ClinVar
REVEL	0.928	moderately pathogenic-leaning
SaProt	LLR -12.11	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 12	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	28.3	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 0.000424% European (non-Finnish) · 5/1,179,920 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,762 alleles · very rare exomes 6/1,461,552 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,232
European (non-Finnish)grpmax	0.000424%	235,984

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg42His
Coding: c.125G>A
MANE Select: NM_000312
dbSNP: rs369504169
Type: single nucleotide variant
Location: chr2:127421337 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 42: a UniProt-annotated variant site (in patients with proc deficiency); a UniProt-annotated variant site (in malakoff; low anticoagulant activity); a UniProt-annotated variant site (in thph3; type ii; osaka-10; alters proteolytic processing so that s-42 is the n-terminus of the mature protein)

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.Arg42Cys Pathogenic/Likely pathogenic ★★ same residue
PROC p.Arg42Leu Likely pathogenic ★ 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-arg42his (accessed [today's date]).

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