Is PAPSS2 p.Ser504= (c.1512C>A) pathogenic?

PAPSS2 p.Ser504= (c.1512C>A) is classified Likely benign in PAPSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). Absent from gnomAD v4.1; Associated with spondyloepimetaphyseal dysplasia, PAPSS2 type.

What condition is associated with PAPSS2 p.Ser504= (c.1512C>A)?

PAPSS2 p.Ser504= (c.1512C>A) is associated with spondyloepimetaphyseal dysplasia, PAPSS2 type (ClinVar).

How common is PAPSS2 p.Ser504= (c.1512C>A) in the general population?

PAPSS2 p.Ser504= (c.1512C>A) is absent from gnomAD v4.1 (gnomAD).

How is Spondyloepimetaphyseal dysplasia, PAPSS2 type inherited?

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

PAPSS2 p.Ser504=

c.1512C>A · VCV4722521

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

spondyloepimetaphyseal dysplasia, PAPSS2 type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.12	GERP -3.8, phastCons 0.47
Overall
CADD	7.581	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PAPSS2
Protein: p.Ser504=
Coding: c.1512C>A
MANE Select: NM_001015880
Type: single nucleotide variant
Location: chr10:87745022 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.35 · 5 PDB
Residue 504: the 'sulfate adenylyltransferase' region

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-ser504 (accessed [today's date]).

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