Is PROC p.Gly423fs (c.1268del) pathogenic?

PROC p.Gly423fs (c.1268del) is classified Pathogenic in PROC (ClinVar, No assertion criteria, 1 submitter; last evaluated 1996-05-15). Very rare (popmax 0.00223%, eas); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Gly423fs (c.1268del)?

PROC p.Gly423fs (c.1268del) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Gly423fs (c.1268del) in the general population?

PROC p.Gly423fs (c.1268del) is very rare (popmax 0.00223%, eas) (gnomAD).

PROC p.Gly423fs

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.1268del · rs1688706133 · VCV670

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 7.8	GERP 2.1, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,842 alleles

Overall 6.2e-05% 1/1,612,298 alleles · very rare exomes 1/1,459,980 · genomes 0/152,318 · joint denominator

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.Gly423fs
Coding: c.1268del
MANE Select: NM_000312
dbSNP: rs1688706133
Type: Deletion
Location: chr2:127428825 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 423: a UniProt-annotated variant site (in thph3); 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.Gly423Ser Likely pathogenic ★ ⚠ same residue
PROC p.Gly423Asp Uncertain significance ★ ⚠ same residue
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.400+9del Benign ★ same condition
PROC c.796+16del Likely benign ★ 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-gly423fs (accessed [today's date]).

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