Is PAPSS2 p.Ser92= (c.276T>C) pathogenic?

PAPSS2 p.Ser92= (c.276T>C) is classified Benign in PAPSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). Low-frequency (popmax 4.71%, eas); Associated with spondyloepimetaphyseal dysplasia, PAPSS2 type.

What condition is associated with PAPSS2 p.Ser92= (c.276T>C)?

PAPSS2 p.Ser92= (c.276T>C) is associated with spondyloepimetaphyseal dysplasia, PAPSS2 type (ClinVar).

How common is PAPSS2 p.Ser92= (c.276T>C) in the general population?

PAPSS2 p.Ser92= (c.276T>C) is low-frequency (popmax 4.71%, eas) (gnomAD).

How is Spondyloepimetaphyseal dysplasia, PAPSS2 type inherited?

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

PAPSS2 p.Ser92=

c.276T>C · rs17124941 · VCV537718

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 4.71%, eas)

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 -1.3	GERP -3.7
Overall
CADD	7.679	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.71% East Asian · 2,101/44,584 alleles

Filtering AF 4.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.48%

Overall 0.327% 5,255/1,609,440 alleles · low-frequency exomes 4,761/1,460,304 · genomes 494/149,136 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	4.71%	21
South Asian	2.14%	47
Remaining individualsnot grpmax-eligible	0.452%	221
Middle Eastern	0.397%	252
Finnishnot grpmax-eligible	0.224%	445
African / African-American	0.138%	724
Admixed American	0.0589%	1,698
European (non-Finnish)	0.0529%	1,892

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.Ser92=
Coding: c.276T>C
MANE Select: NM_001015880
dbSNP: rs17124941
Type: single nucleotide variant
Location: chr10:87713205 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.35 · 5 PDB
Residue 92: the 'adenylyl-sulfate kinase' 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.Ser92Tyr 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-ser92 (accessed [today's date]).

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