Is PAPSS2 p.Pro596Ser (c.1786C>T) pathogenic?

PAPSS2 p.Pro596Ser (c.1786C>T) is classified Uncertain significance in PAPSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-14). AlphaMissense: likely pathogenic (0.9732); Very rare (popmax 0.00576%, nfe); Associated with spondyloepimetaphyseal dysplasia, PAPSS2 type.

What condition is associated with PAPSS2 p.Pro596Ser (c.1786C>T)?

PAPSS2 p.Pro596Ser (c.1786C>T) is associated with spondyloepimetaphyseal dysplasia, PAPSS2 type (ClinVar).

How common is PAPSS2 p.Pro596Ser (c.1786C>T) in the general population?

PAPSS2 p.Pro596Ser (c.1786C>T) is very rare (popmax 0.00576%, nfe) (gnomAD).

How is Spondyloepimetaphyseal dysplasia, PAPSS2 type inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PAPSS2 p.Pro596Ser (c.1786C>T)?

AlphaMissense predicts likely pathogenic (score 0.9732) — an in-silico prediction, not a clinical call.

PAPSS2 p.Pro596Ser

c.1786C>T · rs373121598 · VCV1062853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00576%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

spondyloepimetaphyseal dysplasia, PAPSS2 type

Computational evidence

Protein change
AlphaMissense	0.9732	likely pathogenic
REVEL	0.486	indeterminate
SaProt	LLR -12.66	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 86 kb · p 0.0037 · regional, not allelic
Overall
CADD	24.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P591S vs ClinVar P596S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00576% European (non-Finnish) · 68/1,179,846 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.00428% 69/1,613,906 alleles · very rare exomes 69/1,461,698 · genomes 0/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00576%	17,351
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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: PAPSS2
Protein: p.Pro596Ser
Coding: c.1786C>T
MANE Select: NM_001015880
dbSNP: rs373121598
Type: single nucleotide variant
Location: chr10:87745896 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.35 · 5 PDB
Residue 591 UniProt numbering: the 'sulfate adenylyltransferase' region; an α-helix

Full PAPSS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spondyloepimetaphyseal dysplasia, PAPSS2 type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spondyloepimetaphyseal dysplasia, PAPSS2 type (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PAPSS2 c.640-1G>C Pathogenic/Likely pathogenic ★★ same condition
PAPSS2 p.Arg238Ter Pathogenic/Likely pathogenic ★★ same condition
PAPSS2 p.Arg334Ter Pathogenic ★★ same condition
PAPSS2 p.Arg41Ter Pathogenic ★★ same condition
PAPSS2 p.Tyr492Ter Pathogenic ★★ same condition
PAPSS2 p.Tyr74Ter Pathogenic/Likely pathogenic ★★ same condition
PAPSS2 p.Ala22Val Uncertain significance ★★ ⚠ same condition
PAPSS2 p.Ala409Thr 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/papss2-p-pro596ser (accessed [today's date]).

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