Is UPB1 p.Arg288Pro (c.863G>C) pathogenic?

UPB1 p.Arg288Pro (c.863G>C) is classified Uncertain significance in UPB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.9882); Rare (popmax 0.136%, afr); Associated with Inborn genetic diseases.

What condition is associated with UPB1 p.Arg288Pro (c.863G>C)?

UPB1 p.Arg288Pro (c.863G>C) is associated with Inborn genetic diseases (ClinVar).

How common is UPB1 p.Arg288Pro (c.863G>C) in the general population?

UPB1 p.Arg288Pro (c.863G>C) is rare (popmax 0.136%, afr) (gnomAD).

What do computational predictors say about UPB1 p.Arg288Pro (c.863G>C)?

AlphaMissense predicts likely pathogenic (score 0.9882) — an in-silico prediction, not a clinical call.

UPB1 p.Arg288Pro

c.863G>C · VCV4196447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9882 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9882	likely pathogenic · top 1% in UPB1
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -15.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 30 kb · p 0.76 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.136% African / African-American · 102/75,044 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.107%

Overall 0.00657% 106/1,613,918 alleles · rare exomes 50/1,461,606 · genomes 56/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.136%	736
Admixed American	0.00333%	30,011
Remaining individualsnot grpmax-eligible	0.0032%	31,250

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: UPB1
Protein: p.Arg288Pro
Coding: c.863G>C
MANE Select: NM_016327
Type: single nucleotide variant
Location: chr22:24520458 (GRCh38)
Gene constraint: LOEUF 0.982 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.10 · 2 PDB
Residue 288: the cn hydrolase domain

Full UPB1 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

UPB1 p.Arg288Gln Uncertain significance ★★ ⚠ same residue
UPB1 p.Arg288Ter Likely pathogenic ★ same residue
UPB1 p.Ala4Thr Uncertain significance ★★ ⚠ same condition
UPB1 p.Arg236Gln Uncertain significance ★★ ⚠ same condition
UPB1 p.Arg332Cys Uncertain significance ★★ ⚠ same condition
UPB1 p.Arg332His Uncertain significance ★★ ⚠ same condition
UPB1 p.Arg334Trp Uncertain significance ★★ ⚠ same condition
UPB1 p.Arg68Gln 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/upb1-p-arg288pro (accessed [today's date]).

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