Is PROC p.Ala163Pro (c.487G>C) pathogenic?

PROC p.Ala163Pro (c.487G>C) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-11). AlphaMissense: likely pathogenic (0.699); Absent from gnomAD v4.1.

How common is PROC p.Ala163Pro (c.487G>C) in the general population?

PROC p.Ala163Pro (c.487G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROC p.Ala163Pro (c.487G>C)?

AlphaMissense predicts likely pathogenic (score 0.699) — an in-silico prediction, not a clinical call.

PROC p.Ala163Pro

c.487G>C · rs2468340041 · VCV2506179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.699 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.699	likely pathogenic
REVEL	0.609	indeterminate
SaProt	LLR -8.09	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	22.9	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

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.Ala163Pro
Coding: c.487G>C
MANE Select: NM_000312
dbSNP: rs2468340041
Type: single nucleotide variant
Location: chr2:127423360 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 163: a UniProt-annotated variant site (in thph4; drastically reduced secretion; colocalizes with 26s proteasome); a UniProt-annotated variant site (in thph3; drastically reduced secretion; colocalizes with 26s proteasome); the egf-like 2 domain

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

Similar variants

PROC p.Ala163Ser Uncertain significance ★★ ⚠ same residue
PROC p.Ala163= Likely benign ★ same residue
PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same type
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg199Ter Pathogenic ★★ same type
PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same type

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-ala163pro (accessed [today's date]).

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