Is PGAP3 p.Trp287Cys (c.861G>T) pathogenic?

PGAP3 p.Trp287Cys (c.861G>T) is classified Pathogenic in PGAP3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-03-01). AlphaMissense: likely pathogenic (0.9777); Very rare (popmax 0.00017%, nfe); Associated with hyperphosphatasia with intellectual disability syndrome 4.

What condition is associated with PGAP3 p.Trp287Cys (c.861G>T)?

PGAP3 p.Trp287Cys (c.861G>T) is associated with hyperphosphatasia with intellectual disability syndrome 4 (ClinVar).

How common is PGAP3 p.Trp287Cys (c.861G>T) in the general population?

PGAP3 p.Trp287Cys (c.861G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PGAP3 p.Trp287Cys (c.861G>T)?

AlphaMissense predicts likely pathogenic (score 0.9777) — an in-silico prediction, not a clinical call.

PGAP3 p.Trp287Cys

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.861G>T · rs869312813 · VCV224641

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hyperphosphatasia with intellectual disability syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9777	likely pathogenic ✓ concordant with ClinVar · top 5% in PGAP3
REVEL	0.632	indeterminate
SaProt	LLR -15.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.63 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,178,172 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,609,070 alleles · very rare exomes 1/1,456,908 · genomes 1/152,162 · 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: PGAP3
Protein: p.Trp287Cys
Coding: c.861G>T
MANE Select: NM_033419
dbSNP: rs869312813
Type: single nucleotide variant
Location: chr17:39673089 (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-trp287cys (accessed [today's date]).

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