Is PROC p.His149Pro (c.446A>C) pathogenic?

PROC p.His149Pro (c.446A>C) is classified Pathogenic in PROC (ClinVar, No assertion criteria, 1 submitter; last evaluated 1998-08-01). AlphaMissense: likely pathogenic (0.7419); Very rare (popmax 0.00244%, eas); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.His149Pro (c.446A>C)?

PROC p.His149Pro (c.446A>C) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.His149Pro (c.446A>C) in the general population?

PROC p.His149Pro (c.446A>C) is very rare (popmax 0.00244%, eas) (gnomAD).

What do computational predictors say about PROC p.His149Pro (c.446A>C)?

AlphaMissense predicts likely pathogenic (score 0.7419) — an in-silico prediction, not a clinical call.

PROC p.His149Pro

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.446A>C · rs121918159 · VCV679

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7419 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.7419	likely pathogenic ✓ concordant with ClinVar
REVEL	0.816	moderately pathogenic-leaning
SaProt	LLR -14.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00244% East Asian · 1/40,926 alleles

Overall 6.45e-05% 1/1,549,924 alleles · very rare exomes 0/1,397,760 · genomes 1/152,164 · 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.His149Pro
Coding: c.446A>C
MANE Select: NM_000312
dbSNP: rs121918159
Type: single nucleotide variant
Location: chr2:127423319 (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

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.His149Arg Uncertain significance ★ ⚠ same residue
PROC p.His149fs Pathogenic ★★ same residue
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter Pathogenic ★★ same condition
PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg220Trp 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-his149pro (accessed [today's date]).

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