Is UPB1 p.Pro69Arg (c.206C>G) pathogenic?

UPB1 p.Pro69Arg (c.206C>G) is classified Uncertain significance in UPB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-05). AlphaMissense: likely benign (0.0897); Very rare (popmax 0.00445%, eas); Associated with Inborn genetic diseases.

What condition is associated with UPB1 p.Pro69Arg (c.206C>G)?

UPB1 p.Pro69Arg (c.206C>G) is associated with Inborn genetic diseases (ClinVar).

How common is UPB1 p.Pro69Arg (c.206C>G) in the general population?

UPB1 p.Pro69Arg (c.206C>G) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about UPB1 p.Pro69Arg (c.206C>G)?

AlphaMissense predicts likely benign (score 0.0897) — an in-silico prediction, not a clinical call.

UPB1 p.Pro69Arg

c.206C>G · rs754115355 · VCV2544240

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0897	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -9.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 30 kb · p 0.76 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00445% East Asian · 2/44,904 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,092 alleles · very rare exomes 1/1,461,892 · genomes 1/152,200 · joint denominator

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.Pro69Arg
Coding: c.206C>G
MANE Select: NM_016327
dbSNP: rs754115355
Type: single nucleotide variant
Location: chr22:24500208 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UPB1 p.Pro69Leu Uncertain significance ★ ⚠ same residue
UPB1 p.Ala4Thr Uncertain significance ★★ ⚠ same condition
UPB1 p.Arg236Gln Uncertain significance ★★ ⚠ same condition
UPB1 p.Arg288Gln 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-pro69arg (accessed [today's date]).

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