Is PROC p.Glu56Gln (c.166G>C) pathogenic?

PROC p.Glu56Gln (c.166G>C) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-25). AlphaMissense: likely benign (0.1523); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with PROC p.Glu56Gln (c.166G>C)?

PROC p.Glu56Gln (c.166G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PROC p.Glu56Gln (c.166G>C) in the general population?

PROC p.Glu56Gln (c.166G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PROC p.Glu56Gln (c.166G>C)?

AlphaMissense predicts likely benign (score 0.1523) — an in-silico prediction, not a clinical call.

PROC p.Glu56Gln

c.166G>C · VCV3783503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1523 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1523	likely benign
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -6.68	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	24.9	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 0.0011% South Asian · 1/91,084 alleles

Overall 6.84e-05% 1/1,461,560 alleles · very rare

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.Glu56Gln
Coding: c.166G>C
MANE Select: NM_000312
Type: single nucleotide variant
Location: chr2:127421378 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 56: an α-helix; a modified residue (4-carboxyglutamate); the gla domain

Full PROC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROC p.Asp401Asn Pathogenic/Likely pathogenic ★★ same condition
PROC p.Val339Met Pathogenic ★★ same condition
PROC p.Trp414Arg Uncertain significance ★★ ⚠ same condition
PROC p.Arg189Gly Uncertain significance ★ ⚠ same condition
PROC p.Asn384Ser Uncertain significance ★ ⚠ same condition
PROC p.Asn431Ser Uncertain significance ★ ⚠ same condition
PROC p.Cys101Gly Uncertain significance ★ same condition
PROC p.Glu154Lys Uncertain significance ★ ⚠ 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-glu56gln (accessed [today's date]).

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