Is PGAP2 p.Val84fs (c.251del) pathogenic?

PGAP2 p.Val84fs (c.251del) is classified Pathogenic in PGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-19). Ultra-rare (popmax 0.0379%, nfe); Associated with hyperphosphatasia with intellectual disability syndrome 1.

What condition is associated with PGAP2 p.Val84fs (c.251del)?

PGAP2 p.Val84fs (c.251del) is associated with hyperphosphatasia with intellectual disability syndrome 1 (ClinVar).

How common is PGAP2 p.Val84fs (c.251del) in the general population?

PGAP2 p.Val84fs (c.251del) is ultra-rare (popmax 0.0379%, nfe) (gnomAD).

PGAP2 p.Val84fs

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.251del · VCV4857450

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, nfe)

Conditions

hyperphosphatasia with intellectual disability syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.47	GERP -1.7, phastCons 0.99
Overall
CADD	27.9	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 0.0379% European (non-Finnish) · 447/1,180,030 alleles

Filtering AF 0.0349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0338%

Overall 0.0304% 491/1,614,052 alleles · ultra-rare exomes 444/1,461,870 · genomes 47/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0379%	2,640
Finnishnot grpmax-eligible	0.0375%	2,668
Remaining individualsnot grpmax-eligible	0.0176%	5,680
African / African-American	0.00667%	14,985
Admixed American	0.00667%	14,998

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.Val84fs
Coding: c.251del
MANE Select: NM_014489
Type: Deletion
Location: chr11:3817438 (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 1 — 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.Val84Ile Uncertain significance ★ same residue
PGAP2 p.Gly216Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
PGAP2 c.-60_-57del Pathogenic ★ same type
PGAP2 p.Leu215fs Likely pathogenic ★ same type
PGAP2 c.-32-227_-32-225del Benign ★ same type

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-val84fs (accessed [today's date]).

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