Is PROC p.Ile445Leu (c.1333A>C) pathogenic?

PROC p.Ile445Leu (c.1333A>C) is classified Uncertain significance in PROC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.2525); Ultra-rare (popmax 0.0681%, sas); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Ile445Leu (c.1333A>C)?

PROC p.Ile445Leu (c.1333A>C) is associated with thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

How common is PROC p.Ile445Leu (c.1333A>C) in the general population?

PROC p.Ile445Leu (c.1333A>C) is ultra-rare (popmax 0.0681%, sas) (gnomAD).

What do computational predictors say about PROC p.Ile445Leu (c.1333A>C)?

AlphaMissense predicts likely benign (score 0.2525) — an in-silico prediction, not a clinical call.

PROC p.Ile445Leu

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.1333A>C · rs200012319 · VCV948076

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2525 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.2525	likely benign
REVEL	0.743	pathogenic-leaning
SaProt	LLR -11.52	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 9.3	GERP -0.46, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	22.4	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 0.0681% South Asian · 62/91,084 alleles

Filtering AF 0.0544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0495%

Overall 0.00787% 127/1,613,786 alleles · ultra-rare exomes 122/1,461,652 · genomes 5/152,134 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0681%	1,469
European (non-Finnish)	0.00525%	19,033
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00134%	74,896

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.Ile445Leu
Coding: c.1333A>C
MANE Select: NM_000312
dbSNP: rs200012319
Type: single nucleotide variant
Location: chr2:127428893 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 445: a UniProt-annotated variant site (in patients with proc deficiency); an α-helix; 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

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

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.Ile445Met Likely pathogenic ★ ⚠ same residue
PROC p.Ile445= Likely benign ★ 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-ile445leu (accessed [today's date]).

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