Is PGAP2 p.Arg16Trp (c.46C>T) pathogenic?

PGAP2 p.Arg16Trp (c.46C>T) is classified Pathogenic in PGAP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-04-04). AlphaMissense: ambiguous (0.3702); Very rare (popmax 0.00223%, eas); Associated with hyperphosphatasia with intellectual disability syndrome 3.

What condition is associated with PGAP2 p.Arg16Trp (c.46C>T)?

PGAP2 p.Arg16Trp (c.46C>T) is associated with hyperphosphatasia with intellectual disability syndrome 3 (ClinVar).

How common is PGAP2 p.Arg16Trp (c.46C>T) in the general population?

PGAP2 p.Arg16Trp (c.46C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PGAP2 p.Arg16Trp (c.46C>T)?

AlphaMissense predicts ambiguous (score 0.3702) — an in-silico prediction, not a clinical call.

PGAP2 p.Arg16Trp

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.46C>T · rs773359554 · VCV50505

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hyperphosphatasia with intellectual disability syndrome 3

Computational evidence

Protein change
AlphaMissense	0.3702	ambiguous
REVEL	0.351	indeterminate
SaProt	LLR -12.06	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 161 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	31.0	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 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00304% 49/1,613,918 alleles · very rare exomes 46/1,461,748 · genomes 3/152,170 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0406%	2,462
Remaining individualsnot grpmax-eligible	0.0048%	20,825
East Asiangrpmax	0.00223%	44,890
European (non-Finnish)	0.00153%	65,552
South Asian	0.0011%	91,086

Finnish 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: PGAP2
Protein: p.Arg16Trp
Coding: c.46C>T
MANE Select: NM_014489
dbSNP: rs773359554
Type: single nucleotide variant
Location: chr11:3811305 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00
Residue 16: a UniProt-annotated variant site (in hpmrs3)

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.Arg16Gln 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
PGAP2 c.166-1G>C 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-arg16trp (accessed [today's date]).

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