Is PROC p.Asp297= (c.891C>T) pathogenic?

PROC p.Asp297= (c.891C>T) is classified Benign/Likely benign in PROC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). Low-frequency (popmax 4.4%, eas); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Asp297= (c.891C>T)?

PROC p.Asp297= (c.891C>T) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Asp297= (c.891C>T) in the general population?

PROC p.Asp297= (c.891C>T) is low-frequency (popmax 4.4%, eas) (gnomAD).

PROC p.Asp297=

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.891C>T · rs5935 · VCV237634

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.4%, 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	0.052	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	phastCons 1
Overall
CADD	11.95	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.4% East Asian · 1,975/44,880 alleles

Filtering AF 4.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.17%

Overall 0.248% 4,004/1,614,176 alleles · low-frequency exomes 3,661/1,461,826 · genomes 343/152,350 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	4.4%	23
South Asian	1.92%	52
Remaining individualsnot grpmax-eligible	0.318%	314
Middle Eastern	0.132%	758
African / African-American	0.036%	2,780
Admixed American	0.0183%	5,458
European (non-Finnish)	0.00305%	32,779

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.Asp297=
Coding: c.891C>T
MANE Select: NM_000312
dbSNP: rs5935
Type: single nucleotide variant
Location: chr2:127428451 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 297: a UniProt-annotated variant site (in thph3; also found in patients with proc deficiency; decrease in vitamin-k dependent serine protease activity; decreased golgi localization); 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.Asp297His Pathogenic/Likely 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
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-asp297 (accessed [today's date]).

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