Is PGAP2 p.Leu219= (c.657C>T) pathogenic?

PGAP2 p.Leu219= (c.657C>T) is classified Uncertain significance in PGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-21). Ultra-rare (popmax 0.0657%, mid); Associated with hyperphosphatasia with intellectual disability syndrome 3.

What condition is associated with PGAP2 p.Leu219= (c.657C>T)?

PGAP2 p.Leu219= (c.657C>T) is associated with hyperphosphatasia with intellectual disability syndrome 3 (ClinVar).

How common is PGAP2 p.Leu219= (c.657C>T) in the general population?

PGAP2 p.Leu219= (c.657C>T) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

PGAP2 p.Leu219=

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.657C>T · rs368793106 · VCV1805802

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, 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.
REVEL	0.153	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.46	GERP -0.23, phastCons 0.047
Overall
CADD	6.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00291% 47/1,614,112 alleles · ultra-rare exomes 44/1,461,886 · genomes 3/152,226 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
African / African-American	0.0133%	7,493
Remaining individualsnot grpmax-eligible	0.0096%	10,415
South Asian	0.0022%	45,545
European (non-Finnish)	0.00212%	47,202

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.Leu219=
Coding: c.657C>T
MANE Select: NM_014489
dbSNP: rs368793106
Type: single nucleotide variant
Location: chr11:3824325 (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.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
PGAP2 c.166-1G>C Likely pathogenic ★ same condition
PGAP2 p.Arg246Gln Likely 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/pgap2-p-leu219 (accessed [today's date]).

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