Is PROC p.Glu62Ala (c.185A>C) pathogenic?

PROC p.Glu62Ala (c.185A>C) is classified Pathogenic/Likely pathogenic in PROC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-31). AlphaMissense: likely pathogenic (0.7245); Absent from gnomAD v4.1; Associated with PROC-related disorder.

What condition is associated with PROC p.Glu62Ala (c.185A>C)?

PROC p.Glu62Ala (c.185A>C) is associated with PROC-related disorder, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

How common is PROC p.Glu62Ala (c.185A>C) in the general population?

PROC p.Glu62Ala (c.185A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROC p.Glu62Ala (c.185A>C)?

AlphaMissense predicts likely pathogenic (score 0.7245) — an in-silico prediction, not a clinical call.

PROC p.Glu62Ala

c.185A>C · rs121918148 · VCV664

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7245 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PROC-related disorder

Computational evidence

Protein change
AlphaMissense	0.7245	likely pathogenic ✓ concordant with ClinVar
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -15.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	28.1	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

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.Glu62Ala
Coding: c.185A>C
MANE Select: NM_000312
dbSNP: rs121918148
Type: single nucleotide variant
Location: chr2:127421397 (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

PROC-related disorder

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

Similar variants

PROC p.Glu62= Likely benign ★ same residue
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter 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
PROC p.Arg328Cys 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-glu62ala (accessed [today's date]).

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