Is PGAP3 p.Val155= (c.465T>C) pathogenic?

PGAP3 p.Val155= (c.465T>C) is classified Benign in PGAP3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 76.9%, sas) — too common for a highly-penetrant pathogenic allele; Associated with hyperphosphatasia with intellectual disability syndrome 4.

What condition is associated with PGAP3 p.Val155= (c.465T>C)?

PGAP3 p.Val155= (c.465T>C) is associated with hyperphosphatasia with intellectual disability syndrome 4 (ClinVar).

PGAP3 p.Val155=

Q: How common is PGAP3 p.Val155= (c.465T>C) in the general population?

PGAP3 p.Val155= (c.465T>C) is common (popmax 76.9%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.465T>C · rs2941504 · VCV679984

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 76.9%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

hyperphosphatasia with intellectual disability syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.9	GERP -3.8, phastCons 1
Overall
CADD	9.921	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 76.9% South Asian · 64,541/83,946 alleles

Filtering AF 76.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 76.2%

Overall 68.6% 1,062,933/1,549,746 alleles · common exomes 966,073/1,397,756 · genomes 96,860/151,990 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	81.3%	1
South Asiangrpmax	76.9%	1
Middle Eastern	76.7%	1
Finnishnot grpmax-eligible	72%	1
Ashkenazi Jewishnot grpmax-eligible	70.7%	1
European (non-Finnish)	69.8%	1
Remaining individualsnot grpmax-eligible	67.9%	1
Admixed American	60.1%	2
African / African-American	54.8%	2
East Asian	45.5%	2

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PGAP3
Protein: p.Val155=
Coding: c.465T>C
MANE Select: NM_033419
dbSNP: rs2941504
Type: single nucleotide variant
Location: chr17:39674647 (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 c.558-10G>A Pathogenic/Likely pathogenic ★★ same condition
PGAP3 c.694+1G>A Pathogenic ★★ same condition
PGAP3 p.Asp305Gly Pathogenic/Likely pathogenic ★★ same condition
PGAP3 p.Gln89Ter Pathogenic ★★ same condition
PGAP3 p.Glu37Ter Pathogenic ★★ same condition
PGAP3 p.His284Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
PGAP3 p.His284Tyr Pathogenic/Likely pathogenic ★★ same condition
PGAP3 p.Pro105Gln 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/pgap3-p-val155 (accessed [today's date]).

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