Is PROC p.Arg42Leu (c.125G>T) pathogenic?

PROC p.Arg42Leu (c.125G>T) is classified Likely pathogenic in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-19). AlphaMissense: likely pathogenic (0.6629); Very rare (popmax 0.00017%, nfe).

How common is PROC p.Arg42Leu (c.125G>T) in the general population?

PROC p.Arg42Leu (c.125G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PROC p.Arg42Leu (c.125G>T)?

AlphaMissense predicts likely pathogenic (score 0.6629) — an in-silico prediction, not a clinical call.

PROC p.Arg42Leu

c.125G>T · VCV4540665

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6629	likely pathogenic ✓ concordant with ClinVar
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -11.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	27.0	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 0.00017% European (non-Finnish) · 2/1,179,914 alleles

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

Overall 0.000124% 2/1,613,882 alleles · very rare exomes 2/1,461,554 · genomes 0/152,328 · 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.Arg42Leu
Coding: c.125G>T
MANE Select: NM_000312
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

Similar variants

PROC p.Arg42Cys Pathogenic/Likely pathogenic ★★ same residue
PROC p.Arg42His Likely pathogenic ★★ ⚠ same residue
PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same type
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg199Ter Pathogenic ★★ same type
PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg220Gln Pathogenic/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-arg42leu (accessed [today's date]).

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