Is RPN2 p.Pro4= (c.12G>C) pathogenic?

RPN2 p.Pro4= (c.12G>C) is classified Uncertain significance in RPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-31). Ultra-rare (popmax 0.0595%, nfe); Associated with congenital disorder of glycosylation.

What condition is associated with RPN2 p.Pro4= (c.12G>C)?

RPN2 p.Pro4= (c.12G>C) is associated with congenital disorder of glycosylation (ClinVar).

How common is RPN2 p.Pro4= (c.12G>C) in the general population?

RPN2 p.Pro4= (c.12G>C) is ultra-rare (popmax 0.0595%, nfe) (gnomAD).

RPN2 p.Pro4=

c.12G>C · rs971972758 · VCV2771311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0595%, nfe)

Conditions

congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.082	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.6, phastCons 1
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0595% European (non-Finnish) · 143/240,262 alleles

Filtering AF 0.0515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0485%

Overall 0.0462% 150/324,498 alleles · ultra-rare exomes 146/322,750 · genomes 4/1,748 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0595%	1,680
Remaining individualsnot grpmax-eligible	0.027%	3,703
African / African-American	0.0251%	3,977
Admixed American	0.0108%	9,220

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: RPN2
Protein: p.Pro4=
Coding: c.12G>C
MANE Select: NM_002951
dbSNP: rs971972758
Type: single nucleotide variant
Location: chr20:37179368 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 89.49 · 6 PDB

Full RPN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RPN2 p.Ala558Thr Uncertain significance ★★ ⚠ same condition
RPN2 p.Ala584Ser Uncertain significance ★★ ⚠ same condition
RPN2 p.Arg76Thr Uncertain significance ★★ ⚠ same condition
RPN2 p.Asn497Ser Uncertain significance ★★ ⚠ same condition
RPN2 p.Asn543Ser Uncertain significance ★★ ⚠ same condition
RPN2 p.Asp85Gly Uncertain significance ★★ ⚠ same condition
RPN2 p.Glu182Asp Uncertain significance ★★ ⚠ same condition
RPN2 p.His439Arg 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/rpn2-p-pro4 (accessed [today's date]).

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