Is PROC p.His253Gln (c.759C>A) pathogenic?

PROC p.His253Gln (c.759C>A) is classified Likely pathogenic in PROC (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9805); Very rare (popmax 0.000339%, nfe); Associated with Reduced protein C activity.

What condition is associated with PROC p.His253Gln (c.759C>A)?

PROC p.His253Gln (c.759C>A) is associated with Reduced protein C activity (ClinVar).

How common is PROC p.His253Gln (c.759C>A) in the general population?

PROC p.His253Gln (c.759C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about PROC p.His253Gln (c.759C>A)?

AlphaMissense predicts likely pathogenic (score 0.9805) — an in-silico prediction, not a clinical call.

PROC p.His253Gln

c.759C>A · rs1458669732 · VCV1684347

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Reduced protein C activity

Computational evidence

Protein change
AlphaMissense	0.9805	likely pathogenic ✓ concordant with ClinVar · top 4% in PROC
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -11.70	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 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	24.0	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 0.000339% European (non-Finnish) · 4/1,179,986 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,524 alleles · very rare exomes 2/1,461,312 · genomes 2/152,212 · joint denominator

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.His253Gln
Coding: c.759C>A
MANE Select: NM_000312
dbSNP: rs1458669732
Type: single nucleotide variant
Location: chr2:127427185 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 253: an active site; an α-helix; the peptidase s1 domain; a UniProt-annotated variant site (in patients with proc deficiency)

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.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
PROC p.Val26Met Likely pathogenic ★ ⚠ same condition
PROC p.Ala388Val Conflicting classifications of pathogenicity ★ ⚠ 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-his253gln (accessed [today's date]).

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