Is PGAP2 p.Glu131Ter (c.391G>T) pathogenic?

PGAP2 p.Glu131Ter (c.391G>T) is classified Pathogenic in PGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-23). Ultra-rare (popmax 0.0165%, mid); Associated with hyperphosphatasia with intellectual disability syndrome 3.

What condition is associated with PGAP2 p.Glu131Ter (c.391G>T)?

PGAP2 p.Glu131Ter (c.391G>T) is associated with hyperphosphatasia with intellectual disability syndrome 3 (ClinVar).

How common is PGAP2 p.Glu131Ter (c.391G>T) in the general population?

PGAP2 p.Glu131Ter (c.391G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

PGAP2 p.Glu131Ter

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.391G>T · rs1590414630 · VCV827783

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

hyperphosphatasia with intellectual disability syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 7
REVEL	0.208	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.09 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Overall 6.24e-05% 1/1,603,576 alleles · ultra-rare exomes 1/1,451,340 · genomes 0/152,236 · joint denominator

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: PGAP2
Protein: p.Glu131Ter
Coding: c.391G>T
MANE Select: NM_014489
dbSNP: rs1590414630
Type: single nucleotide variant
Location: chr11:3823925 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00

Full PGAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperphosphatasia with intellectual disability syndrome 3 — 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

PGAP2 p.Glu131Gly Uncertain significance ★ ⚠ same residue
PGAP2 p.Glu131fs Uncertain significance ★ same residue
PGAP2 p.Ala127Val Likely pathogenic ★★ same condition
PGAP2 p.Arg238Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
PGAP2 p.Thr294Met Likely pathogenic ★★ same condition
PGAP2 c.602-3C>T Uncertain significance ★★ same condition
PGAP2 p.Asn205Lys Uncertain significance ★★ ⚠ same condition
PGAP2 p.Ser257Leu 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/pgap2-p-glu131ter (accessed [today's date]).

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