Is PGAP3 p.Arg159Ser (c.477G>C) pathogenic?

PGAP3 p.Arg159Ser (c.477G>C) is classified Conflicting classifications of pathogenicity in PGAP3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.9562); Rare (popmax 0.235%, afr); Associated with hyperphosphatasia with intellectual disability syndrome 4.

What condition is associated with PGAP3 p.Arg159Ser (c.477G>C)?

PGAP3 p.Arg159Ser (c.477G>C) is associated with hyperphosphatasia with intellectual disability syndrome 4 (ClinVar).

How common is PGAP3 p.Arg159Ser (c.477G>C) in the general population?

PGAP3 p.Arg159Ser (c.477G>C) is rare (popmax 0.235%, afr) (gnomAD).

What do computational predictors say about PGAP3 p.Arg159Ser (c.477G>C)?

AlphaMissense predicts likely pathogenic (score 0.9562) — an in-silico prediction, not a clinical call.

PGAP3 p.Arg159Ser

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.477G>C · rs150483675 · VCV373161

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9562 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.235%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hyperphosphatasia with intellectual disability syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9562	likely pathogenic · top 10% in PGAP3
REVEL	0.366	indeterminate
SaProt	LLR -12.14	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 1.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.63 · regional, not allelic
Overall
CADD	26.3	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 0.235% African / African-American · 172/73,140 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.195%

Overall 0.0115% 178/1,551,286 alleles · rare exomes 75/1,399,052 · genomes 103/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.235%	425
Admixed American	0.00588%	16,993
Remaining individualsnot grpmax-eligible	0.00333%	30,050
European (non-Finnish)	8.72e-05%	1,146,680

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.Arg159Ser
Coding: c.477G>C
MANE Select: NM_033419
dbSNP: rs150483675
Type: single nucleotide variant
Location: chr17:39674635 (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-arg159ser (accessed [today's date]).

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