Is PROC p.Cys373fs (c.1115dup) pathogenic?

PROC p.Cys373fs (c.1115dup) is classified Pathogenic in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-01). Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Cys373fs (c.1115dup)?

PROC p.Cys373fs (c.1115dup) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

PROC p.Cys373fs

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.1115dup · VCV4698752

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (9 of 9) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	phastCons 0.91

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: PROC
Protein: p.Cys373fs
Coding: c.1115dup
MANE Select: NM_000312
Type: Duplication
Location: chr2:127428674 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 373: an α-helix; 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.Cys373Ser Uncertain significance ★ ⚠ same residue
PROC p.His149fs Pathogenic ★★ same condition
PROC p.Pro405fs Pathogenic/Likely pathogenic ★★ same condition
PROC p.Cys373Arg Likely pathogenic ★ same residue
PROC p.Lys234fs Pathogenic ★ same condition
PROC c.400+9dup Benign ★ same condition
PROC c.535+13dup Benign ★ same condition
PROC p.Ala309Thr 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-cys373fs (accessed [today's date]).

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