Is PAPSS2 p.Phe283= (c.849T>C) pathogenic?

PAPSS2 p.Phe283= (c.849T>C) is classified Likely benign in PAPSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-09). Ultra-rare (popmax 0.0484%, amr); Associated with spondyloepimetaphyseal dysplasia, PAPSS2 type.

What condition is associated with PAPSS2 p.Phe283= (c.849T>C)?

PAPSS2 p.Phe283= (c.849T>C) is associated with spondyloepimetaphyseal dysplasia, PAPSS2 type (ClinVar).

How common is PAPSS2 p.Phe283= (c.849T>C) in the general population?

PAPSS2 p.Phe283= (c.849T>C) is ultra-rare (popmax 0.0484%, amr) (gnomAD).

How is Spondyloepimetaphyseal dysplasia, PAPSS2 type inherited?

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

PAPSS2 p.Phe283=

c.849T>C · rs529851319 · VCV1640274

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0484%, amr)

Conditions

spondyloepimetaphyseal dysplasia, PAPSS2 type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.28	donor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -2.6	GERP -3.8
Overall
CADD	5.023	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0484% Admixed American · 29/59,962 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00189% 30/1,590,980 alleles · ultra-rare exomes 18/1,438,664 · genomes 12/152,316 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0484%	2,068
Remaining individualsnot grpmax-eligible	0.00162%	61,690

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.Phe283=
Coding: c.849T>C
MANE Select: NM_001015880
dbSNP: rs529851319
Type: single nucleotide variant
Location: chr10:87715827 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.35 · 5 PDB
Residue 283: 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-phe283 (accessed [today's date]).

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