Is PROC p.Pro461fs (c.1378_1379dup) pathogenic?

PROC p.Pro461fs (c.13781379dup) is classified Likely pathogenic in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-01). Absent from gnomAD; Associated with Reduced protein C activity.

What condition is associated with PROC p.Pro461fs (c.1378_1379dup)?

PROC p.Pro461fs (c.1378_1379dup) is associated with Reduced protein C activity (ClinVar).

How common is PROC p.Pro461fs (c.1378_1379dup) in the general population?

PROC p.Pro461fs (c.1378_1379dup) is absent from gnomAD (gnomAD).

PROC p.Pro461fs

c.1378_1379dup · rs1573462001 · VCV626997

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Reduced protein C activity

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 0.62	GERP -1.5

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.Pro461fs
Coding: c.1378_1379dup
MANE Select: NM_000312
dbSNP: rs1573462001
Type: Duplication
Location: chr2:127428937 (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

Reduced protein C activity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same condition
PROC p.Cys147Tyr Likely pathogenic ★★ same condition
PROC c.797-2A>T Likely pathogenic ★ same condition
PROC p.Lys457fs Likely pathogenic ★ same condition
PROC p.Ser141Pro Likely pathogenic ★ same condition
PROC p.Thr340Lys Likely pathogenic ★ same condition
PROC p.Trp444Ter Likely pathogenic ★ same condition
PROC p.Val26Met 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-pro461fs (accessed [today's date]).

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