Is RPN2 p.Ser280= (c.840C>T) pathogenic?

RPN2 p.Ser280= (c.840C>T) is classified Likely benign in RPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-16). Very rare (popmax 0.004%, afr); Associated with congenital disorder of glycosylation.

What condition is associated with RPN2 p.Ser280= (c.840C>T)?

RPN2 p.Ser280= (c.840C>T) is associated with congenital disorder of glycosylation (ClinVar).

How common is RPN2 p.Ser280= (c.840C>T) in the general population?

RPN2 p.Ser280= (c.840C>T) is very rare (popmax 0.004%, afr) (gnomAD).

RPN2 p.Ser280=

c.840C>T · rs535586576 · VCV1133460

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.7	GERP -3.5
Overall
CADD	0.238	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,054 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00211% 34/1,614,190 alleles · very rare exomes 31/1,461,862 · genomes 3/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,018
European (non-Finnish)	0.00246%	40,690
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asian	0.0011%	91,086

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.Ser280=
Coding: c.840C>T
MANE Select: NM_002951
dbSNP: rs535586576
Type: single nucleotide variant
Location: chr20:37207422 (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-ser280 (accessed [today's date]).

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