Is PAPSS2 p.Pro519= (c.1557T>C) pathogenic?

PAPSS2 p.Pro519= (c.1557T>C) is classified Likely benign in PAPSS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-08). Ultra-rare (popmax 0.033%, mid); Associated with spondyloepimetaphyseal dysplasia, PAPSS2 type.

What condition is associated with PAPSS2 p.Pro519= (c.1557T>C)?

PAPSS2 p.Pro519= (c.1557T>C) is associated with spondyloepimetaphyseal dysplasia, PAPSS2 type (ClinVar).

How common is PAPSS2 p.Pro519= (c.1557T>C) in the general population?

PAPSS2 p.Pro519= (c.1557T>C) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Spondyloepimetaphyseal dysplasia, PAPSS2 type inherited?

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

PAPSS2 p.Pro519=

c.1557T>C · rs748087437 · VCV1557433

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

spondyloepimetaphyseal dysplasia, PAPSS2 type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -0.93
Overall
CADD	5.085	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.0013% 21/1,614,082 alleles · ultra-rare exomes 19/1,461,832 · genomes 2/152,250 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)	0.00136%	73,748
South Asian	0.0011%	91,076

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.Pro519=
Coding: c.1557T>C
MANE Select: NM_001015880
dbSNP: rs748087437
Type: single nucleotide variant
Location: chr10:87745067 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.35 · 5 PDB
Residue 519: 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 p.Pro519Thr Uncertain significance ★ ⚠ same residue
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

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-pro519 (accessed [today's date]).

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