Is PROC p.Leu391= (c.1173C>T) pathogenic?

PROC p.Leu391= (c.1173C>T) is classified Likely benign in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-22). Very rare (popmax 0.000678%, nfe); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Leu391= (c.1173C>T)?

PROC p.Leu391= (c.1173C>T) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Leu391= (c.1173C>T) in the general population?

PROC p.Leu391= (c.1173C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

PROC p.Leu391=

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.1173C>T · VCV3704197

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000678%, 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.
REVEL	0.107	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.5
Overall
CADD	1.324	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,180,020 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,594 alleles · very rare exomes 8/1,461,246 · genomes 0/152,348 · 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.Leu391=
Coding: c.1173C>T
MANE Select: NM_000312
Type: single nucleotide variant
Location: chr2:127428733 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 391: 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.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
PROC p.Arg271Trp Pathogenic/Likely pathogenic ★★ same condition
PROC p.Arg272Cys 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-leu391 (accessed [today's date]).

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