Is PROC p.His149fs (c.445dup) pathogenic?

PROC p.His149fs (c.445dup) is classified Pathogenic in PROC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-07). Very rare (popmax 0.00061%, nfe); Associated with PROC-related disorder.

What condition is associated with PROC p.His149fs (c.445dup)?

PROC p.His149fs (c.445dup) is associated with PROC-related disorder, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.His149fs (c.445dup) in the general population?

PROC p.His149fs (c.445dup) is very rare (popmax 0.00061%, nfe) (gnomAD).

PROC p.His149fs

c.445dup · rs772629538 · VCV1389677

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00061%, nfe)

Conditions

PROC-related disorder

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 6 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.8

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00061% European (non-Finnish) · 7/1,146,970 alleles

Filtering AF 0.000254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000452% 7/1,550,080 alleles · very rare exomes 7/1,397,772 · genomes 0/152,308 · 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.His149fs
Coding: c.445dup
MANE Select: NM_000312
dbSNP: rs772629538
Type: Duplication
Location: chr2:127423317 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 149: a β-strand; a UniProt-annotated variant site (in patients with proc deficiency); the egf-like 2 domain

Full PROC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PROC-related disorder

Also linked: thrombophilia due to protein C deficiency, autosomal dominant

Similar variants

PROC p.His149Arg Uncertain significance ★ ⚠ same residue
PROC p.His149Pro Pathogenic same residue
PROC p.Pro405fs Pathogenic/Likely pathogenic ★★ same condition
PROC p.Cys373fs Pathogenic ★ same condition
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-his149fs (accessed [today's date]).

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