Is PROC p.Val417Met (c.1249G>A) pathogenic?

PROC p.Val417Met (c.1249G>A) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-16). AlphaMissense: likely benign (0.2894); Very rare (popmax 0.00424%, nfe); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Val417Met (c.1249G>A)?

PROC p.Val417Met (c.1249G>A) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Val417Met (c.1249G>A) in the general population?

PROC p.Val417Met (c.1249G>A) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about PROC p.Val417Met (c.1249G>A)?

AlphaMissense predicts likely benign (score 0.2894) — an in-silico prediction, not a clinical call.

PROC p.Val417Met

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.1249G>A · rs144760718 · VCV2883556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2894 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.2894	likely benign
REVEL	0.669	pathogenic-leaning
SaProt	LLR -9.41	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 12	GERP -0.88, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	26.5	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 0.00424% European (non-Finnish) · 50/1,178,966 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00343% 50/1,459,846 alleles · very rare

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.Val417Met
Coding: c.1249G>A
MANE Select: NM_000312
dbSNP: rs144760718
Type: single nucleotide variant
Location: chr2:127428809 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 417: a β-strand; a disulfide bond; the peptidase s1 domain

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

Disease context

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

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.Val417Leu 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-val417met (accessed [today's date]).

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