Is PROC p.Ala251Glu (c.752C>A) pathogenic?

PROC p.Ala251Glu (c.752C>A) is classified Likely pathogenic in PROC (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9712); Absent from gnomAD v4.1; Associated with Reduced protein C activity.

What condition is associated with PROC p.Ala251Glu (c.752C>A)?

PROC p.Ala251Glu (c.752C>A) is associated with Reduced protein C activity (ClinVar).

How common is PROC p.Ala251Glu (c.752C>A) in the general population?

PROC p.Ala251Glu (c.752C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROC p.Ala251Glu (c.752C>A)?

AlphaMissense predicts likely pathogenic (score 0.9712) — an in-silico prediction, not a clinical call.

PROC p.Ala251Glu

c.752C>A · rs568121876 · VCV1684348

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9712 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Reduced protein C activity

Computational evidence

Protein change
AlphaMissense	0.9712	likely pathogenic ✓ concordant with ClinVar · top 6% in PROC
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -14.49	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	25.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PROC
Protein: p.Ala251Glu
Coding: c.752C>A
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

Reduced protein C activity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROC p.Ala251Val Conflicting classifications of pathogenicity ★ ⚠ same residue
PROC p.Ala251= Likely benign ★ same residue
PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same condition
PROC p.Cys147Tyr Likely pathogenic ★★ same condition
PROC c.797-2A>T Likely pathogenic ★ same condition
PROC p.Ser141Pro Likely pathogenic ★ same condition
PROC p.Thr340Lys Likely pathogenic ★ same condition
PROC p.Trp444Ter 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-ala251glu (accessed [today's date]).

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