Is UPB1 p.Arg70Pro (c.209G>C) pathogenic?

UPB1 p.Arg70Pro (c.209G>C) is classified Likely pathogenic in UPB1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-06-20). AlphaMissense: likely pathogenic (0.6387); Ultra-rare (popmax 0.0236%, nfe); Associated with UPB1-related disorder.

What condition is associated with UPB1 p.Arg70Pro (c.209G>C)?

UPB1 p.Arg70Pro (c.209G>C) is associated with UPB1-related disorder, beta-ureidopropionase deficiency (ClinVar).

How common is UPB1 p.Arg70Pro (c.209G>C) in the general population?

UPB1 p.Arg70Pro (c.209G>C) is ultra-rare (popmax 0.0236%, nfe) (gnomAD).

What do computational predictors say about UPB1 p.Arg70Pro (c.209G>C)?

AlphaMissense predicts likely pathogenic (score 0.6387) — an in-silico prediction, not a clinical call.

UPB1 p.Arg70Pro

c.209G>C · rs121908066 · VCV4150

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6387 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0236%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

UPB1-related disorder

Computational evidence

Protein change
AlphaMissense	0.6387	likely pathogenic ✓ concordant with ClinVar
REVEL	0.511	indeterminate
SaProt	LLR -13.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP -2.4
Regional constraint	o/e 0.99	unconstrained · MANE · 30 kb · p 0.76 · regional, not allelic
Overall
CADD	21.1	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 0.0236% European (non-Finnish) · 278/1,180,032 alleles

Filtering AF 0.0213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0204%

Overall 0.0186% 300/1,614,098 alleles · ultra-rare exomes 284/1,461,894 · genomes 16/152,204 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0336%	2,976
European (non-Finnish)grpmax	0.0236%	4,245
African / African-American	0.00133%	74,936

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg70Pro
Coding: c.209G>C
MANE Select: NM_016327
dbSNP: rs121908066
Type: single nucleotide variant
Location: chr22:24500211 (GRCh38)
Gene constraint: LOEUF 0.982 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.10 · 2 PDB

Full UPB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

UPB1-related disorder

Also linked: beta-ureidopropionase deficiency

Similar variants

UPB1 p.Arg70His Uncertain significance ★ ⚠ same residue
UPB1 p.Arg70Cys Uncertain significance ★★ ⚠ same residue
UPB1 c.873+1G>A Pathogenic/Likely pathogenic ★★ same condition
UPB1 c.917-1G>A Pathogenic/Likely pathogenic ★★ same condition
UPB1 p.Asn345Ile Likely pathogenic ★★ same condition
UPB1 p.Gln118Ter Pathogenic ★★ same condition
UPB1 c.-27G>C Uncertain significance ★★ same condition
UPB1 p.Ala2Gly 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-arg70pro (accessed [today's date]).

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