Is PROC p.Asp256= (c.768T>C) pathogenic?

PROC p.Asp256= (c.768T>C) is classified Benign in PROC (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 35.4%, mid) — too common for a highly-penetrant pathogenic allele; Associated with thrombophilia due to protein C deficiency, autosomal recessive.

What condition is associated with PROC p.Asp256= (c.768T>C)?

PROC p.Asp256= (c.768T>C) is associated with thrombophilia due to protein C deficiency, autosomal recessive, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

PROC p.Asp256=

Q: How common is PROC p.Asp256= (c.768T>C) in the general population?

PROC p.Asp256= (c.768T>C) is common (popmax 35.4%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.768T>C · rs5937 · VCV255810

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 35.4%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

thrombophilia due to protein C deficiency, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.61
Overall
CADD	0.945	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.4% Middle Eastern · 2,133/6,020 alleles

Filtering AF 34.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 33.7%

Overall 31% 500,581/1,612,832 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	35.4%	3
Amishnot grpmax-eligible	35.1%	3
Ashkenazi Jewishnot grpmax-eligible	34.8%	3
European (non-Finnish)	32.9%	3
African / African-American	32.3%	3
Remaining individualsnot grpmax-eligible	30%	3
Finnishnot grpmax-eligible	29.3%	3
South Asian	29.1%	3
Admixed American	19%	5
East Asian	0.185%	541

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.Asp256=
Coding: c.768T>C
MANE Select: NM_000312
dbSNP: rs5937
Type: single nucleotide variant
Location: chr2:127427194 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 256: a disulfide bond; 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 recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

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.Asp256Glu Uncertain significance ⚠ 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-asp256 (accessed [today's date]).

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