Is PROC c.400+9del pathogenic?

PROC c.400+9del is classified Benign in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-11). Very rare (popmax 9.26e-05%, nfe); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC c.400+9del?

PROC c.400+9del is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC c.400+9del in the general population?

PROC c.400+9del is very rare (popmax 9.26e-05%, nfe) (gnomAD).

PROC c.400+9del

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.

rs746387774 · VCV3020627

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 9.26e-05%, nfe)

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.
Splicing
Splice region	donor +9	near-intronic (+9 nt from the splice site)
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.4	phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.26e-05% European (non-Finnish) · 1/1,079,558 alleles

Overall 0.000138% 2/1,447,268 alleles · very rare exomes 2/1,304,046 · genomes 0/143,222 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00188%	53,076
European (non-Finnish)grpmax	9.26e-05%	1,079,558

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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
Coding: c.400+9del
MANE Select: NM_000312
dbSNP: rs746387774
Type: Deletion
Location: chr2:127423176 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB

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.Leu303fs Pathogenic/Likely pathogenic ★★ same condition
PROC p.Asp113_Ile115del Uncertain significance ★ same condition
PROC p.Ser119_Ser124del Conflicting classifications of pathogenicity ★ same condition
PROC p.Val434_Tyr435insTer Uncertain significance ★ same condition
PROC c.796+16del Likely benign ★ same condition
PROC p.Gly423fs Pathogenic same condition
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter 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-c-400-plus-9del (accessed [today's date]).

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