Is PROC p.Ala251Val (c.752C>T) pathogenic?

PROC p.Ala251Val (c.752C>T) is classified Conflicting classifications of pathogenicity in PROC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2020-01-08). AlphaMissense: likely pathogenic (0.6673); Rare (popmax 0.159%, sas); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Ala251Val (c.752C>T)?

PROC p.Ala251Val (c.752C>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.Ala251Val (c.752C>T) in the general population?

PROC p.Ala251Val (c.752C>T) is rare (popmax 0.159%, sas) (gnomAD).

What do computational predictors say about PROC p.Ala251Val (c.752C>T)?

AlphaMissense predicts likely pathogenic (score 0.6673) — an in-silico prediction, not a clinical call.

PROC p.Ala251Val

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.752C>T · rs568121876 · VCV810674

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6673 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.159%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.6673	likely pathogenic
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -11.00	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 2.7	phastCons 0.99
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	25.1	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 0.159% South Asian · 145/91,080 alleles

Filtering AF 0.138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.13%

Overall 0.0112% 181/1,613,604 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.159%	628
Middle Eastern	0.0165%	6,056
East Asian	0.0111%	8,974
Admixed American	0.00666%	15,007
African / African-American	0.00666%	15,013
Remaining individualsnot grpmax-eligible	0.0064%	15,625
European (non-Finnish)	0.00144%	69,409

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.Ala251Val
Coding: c.752C>T
MANE Select: NM_000312
dbSNP: rs568121876
Type: single nucleotide variant
Location: chr2:127427178 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 251: 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.Ala251= Likely benign ★ same residue
PROC p.Ala251Glu 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

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-ala251val (accessed [today's date]).

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