Is PROC p.Ala309= (c.927C>T) pathogenic?

PROC p.Ala309= (c.927C>T) is classified Benign/Likely benign in PROC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Rare (popmax 0.446%, eas); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Ala309= (c.927C>T)?

PROC p.Ala309= (c.927C>T) is associated with thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

How common is PROC p.Ala309= (c.927C>T) in the general population?

PROC p.Ala309= (c.927C>T) is rare (popmax 0.446%, eas) (gnomAD).

PROC p.Ala309=

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.927C>T · rs200731614 · VCV331109

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.446%, 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.
REVEL	0.076	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12
Overall
CADD	3.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.446% East Asian · 200/44,886 alleles

Filtering AF 0.395% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.376%

Overall 0.0145% 234/1,614,142 alleles · rare exomes 209/1,461,756 · genomes 25/152,386 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.446%	224
South Asian	0.0252%	3,960
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.00167%	60,032

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.Ala309=
Coding: c.927C>T
MANE Select: NM_000312
dbSNP: rs200731614
Type: single nucleotide variant
Location: chr2:127428487 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 309: a UniProt-annotated variant site (in patients with proc deficiency); an α-helix; 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

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

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 residue
PROC p.Ala309Pro Uncertain significance ★ same residue
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

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-ala309 (accessed [today's date]).

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