Is UPB1 p.Pro322Ser (c.964C>T) pathogenic?

UPB1 p.Pro322Ser (c.964C>T) is classified Uncertain significance in UPB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.6917); Very rare (popmax 0.000124%); Associated with Inborn genetic diseases.

What condition is associated with UPB1 p.Pro322Ser (c.964C>T)?

UPB1 p.Pro322Ser (c.964C>T) is associated with Inborn genetic diseases (ClinVar).

How common is UPB1 p.Pro322Ser (c.964C>T) in the general population?

UPB1 p.Pro322Ser (c.964C>T) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about UPB1 p.Pro322Ser (c.964C>T)?

AlphaMissense predicts likely pathogenic (score 0.6917) — an in-silico prediction, not a clinical call.

UPB1 p.Pro322Ser

c.964C>T · VCV4196455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6917	likely pathogenic
REVEL	0.911	moderately pathogenic-leaning
SaProt	LLR -13.28	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 4.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 30 kb · p 0.76 · regional, not allelic
Overall
CADD	24.5	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 0.000124%

Overall 0.000124% 2/1,614,270 alleles · very rare exomes 2/1,461,888 · genomes 0/152,382 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0016%	62,512

Ashkenazi Jewish 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.Pro322Ser
Coding: c.964C>T
MANE Select: NM_016327
Type: single nucleotide variant
Location: chr22:24523666 (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 322: 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.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
UPB1 p.Arg70Cys 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-pro322ser (accessed [today's date]).

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