Is PROC p.Cys111fs (c.326_330dup) pathogenic?

PROC p.Cys111fs (c.326330dup) is classified Pathogenic in PROC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). No gnomAD frequency available for this variant; Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Cys111fs (c.326_330dup)?

PROC p.Cys111fs (c.326_330dup) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Cys111fs (c.326_330dup) in the general population?

PROC p.Cys111fs (c.326_330dup) is no gnomAD frequency available for this variant (gnomAD).

PROC p.Cys111fs

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.326_330dup · rs1688218776 · VCV838069

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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	predicted	premature termination codon in exon 5 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.7	phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PROC
Protein: p.Cys111fs
Coding: c.326_330dup
MANE Select: NM_000312
dbSNP: rs1688218776
Type: Microsatellite
Location: chr2:127423090 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 111: a β-strand; a disulfide bond; the egf-like 1 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.Gln207_Val208insGluAspGln Uncertain significance ★ same condition
PROC p.Glu62del Uncertain significance ★ same condition
PROC p.Lys193del Conflicting classifications of pathogenicity ★ same condition
PROC p.Lys235del Uncertain significance ★ same condition
PROC c.238-12CT[2] Likely benign ★ same condition
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter Pathogenic ★★ same condition
PROC p.Arg211Gln 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-cys111fs (accessed [today's date]).

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