Is PROC p.Arg129His (c.386G>A) pathogenic?

PROC p.Arg129His (c.386G>A) is classified Uncertain significance in PROC (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-03-25). AlphaMissense: likely benign (0.0861); Ultra-rare (popmax 0.0173%, mid); Associated with PROC-related disorder.

How common is PROC p.Arg129His (c.386G>A) in the general population?

PROC p.Arg129His (c.386G>A) is ultra-rare (popmax 0.0173%, mid) (gnomAD).

What do computational predictors say about PROC p.Arg129His (c.386G>A)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

PROC p.Arg129His

Q: What condition is associated with PROC p.Arg129His (c.386G>A)?

PROC p.Arg129His (c.386G>A) is associated with PROC-related disorder, thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

c.386G>A · rs746190838 · VCV627207

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PROC-related disorder

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.654	pathogenic-leaning
SaProt	LLR -7.92	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	24.1	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 0.0173% Middle Eastern · 1/5,794 alleles

Filtering AF 0.00242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00212%

Overall 0.00295% 47/1,591,734 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0173%	5,794
Remaining individualsnot grpmax-eligible	0.00652%	15,335
South Asian	0.00337%	29,673
European (non-Finnish)	0.00325%	30,753
African / African-American	0.00135%	73,980

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.Arg129His
Coding: c.386G>A
MANE Select: NM_000312
dbSNP: rs746190838
Type: single nucleotide variant
Location: chr2:127423157 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 129: a disulfide bond; the egf-like 1 domain

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

Disease context

PROC-related disorder

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

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-arg129his (accessed [today's date]).

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