Is UPB1 p.Pro18Leu (c.53C>T) pathogenic?

UPB1 p.Pro18Leu (c.53C>T) is classified Uncertain significance in UPB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-01). AlphaMissense: likely benign (0.1254); Very rare (popmax 0.00542%, nfe).

How common is UPB1 p.Pro18Leu (c.53C>T) in the general population?

UPB1 p.Pro18Leu (c.53C>T) is very rare (popmax 0.00542%, nfe) (gnomAD).

What do computational predictors say about UPB1 p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.1254) — an in-silico prediction, not a clinical call.

UPB1 p.Pro18Leu

c.53C>T · VCV3905437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1254 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1254	likely benign
REVEL	0.414	indeterminate
SaProt	LLR -9.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 30 kb · p 0.76 · regional, not allelic
Overall
CADD	22.2	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 0.00542% European (non-Finnish) · 64/1,180,034 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.00428% 69/1,613,920 alleles · very rare exomes 63/1,461,716 · genomes 6/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00542%	18,438
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,468
East Asian	0.00223%	44,896

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.Pro18Leu
Coding: c.53C>T
MANE Select: NM_016327
Type: single nucleotide variant
Location: chr22:24495456 (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

Similar variants

UPB1 p.Pro18= Conflicting classifications of pathogenicity ★ same residue
UPB1 c.873+1G>A Pathogenic/Likely pathogenic ★★ same type
UPB1 c.917-1G>A Pathogenic/Likely pathogenic ★★ same type
UPB1 p.Asn345Ile Likely pathogenic ★★ same type
UPB1 p.Gln118Ter Pathogenic ★★ same type
UPB1 c.-27G>C Uncertain significance ★★ same type
UPB1 p.Ala2Gly Uncertain significance ★★ ⚠ same type
UPB1 p.Ala4Thr Uncertain significance ★★ ⚠ same type

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-pro18leu (accessed [today's date]).

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