Is PGAP3 p.Ser300fs (c.896dup) pathogenic?

PGAP3 p.Ser300fs (c.896dup) is classified Likely pathogenic in PGAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-16). Ultra-rare (gnomAD MAF 1.707e-06); Associated with hyperphosphatasia with intellectual disability syndrome 4.

What condition is associated with PGAP3 p.Ser300fs (c.896dup)?

PGAP3 p.Ser300fs (c.896dup) is associated with hyperphosphatasia with intellectual disability syndrome 4 (ClinVar).

How common is PGAP3 p.Ser300fs (c.896dup) in the general population?

PGAP3 p.Ser300fs (c.896dup) is ultra-rare (gnomAD MAF 1.707e-06) (gnomAD).

PGAP3 p.Ser300fs

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.896dup · rs2543759733 · VCV1802697

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (gnomAD MAF 1.707e-06)

Conditions

hyperphosphatasia with intellectual disability syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (7 of 8, 2 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

Global frequency 0.000171% via dbSNP · ultra-rare

No ancestry breakdown or filtering allele frequency is available for this variant, so BA1/BS1 cannot be assessed from this figure alone.

Variant & gene context

Gene: PGAP3
Protein: p.Ser300fs
Coding: c.896dup
MANE Select: NM_033419
dbSNP: rs2543759733
Type: Duplication
Location: chr17:39673053 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.17

Full PGAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperphosphatasia with intellectual disability syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperphosphatasia-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PGAP3 p.Met135fs Pathogenic ★★ same condition
PGAP3 p.Trp152fs Pathogenic ★★ same condition
PGAP3 p.Cys68fs Likely pathogenic ★ same condition
PGAP3 p.Val28fs Pathogenic ★ same condition
PER1 p.Arg300Cys Uncertain significance ★ ⚠ same residue
PER1 p.Arg300His Uncertain significance ★ ⚠ same residue
PGAP3 p.Ser300Gly Uncertain significance ★ ⚠ same residue
PGAP3 p.Leu147fs Pathogenic 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/pgap3-p-ser300fs (accessed [today's date]).

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