Is PROC p.Glu62del (c.181GAG[1]) pathogenic?

PROC p.Glu62del (c.181GAG[1]) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-06). Very rare (popmax 0.00445%, eas); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Glu62del (c.181GAG[1])?

PROC p.Glu62del (c.181GAG[1]) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Glu62del (c.181GAG[1]) in the general population?

PROC p.Glu62del (c.181GAG[1]) is very rare (popmax 0.00445%, eas) (gnomAD).

PROC p.Glu62del

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.181GAG[1] · VCV4709316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00445%, 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.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.63

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000186% 3/1,613,952 alleles · very rare exomes 3/1,461,596 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
South Asian	0.0011%	91,084

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.Glu62del
Coding: c.181GAG[1]
MANE Select: NM_000312
Type: Microsatellite
Location: chr2:127421393 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 62: a modified residue (4-carboxyglutamate); a UniProt-annotated variant site (in thph3; vermont-1); the gla 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.Glu62= Likely benign ★ same residue
PROC p.Cys111fs Pathogenic ★★ same condition
PROC p.Glu62Ala Pathogenic/Likely pathogenic ★★ same residue
PROC p.Gln207_Val208insGluAspGln Uncertain significance ★ same condition
PROC p.Lys193del Conflicting classifications of pathogenicity ★ same condition
PROC p.Lys235del Uncertain significance ★ same condition
PROC c.238-12CT[2] Likely benign ★ same condition
PROC p.Ala309Thr 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-glu62del (accessed [today's date]).

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