Is PGAP2 p.Arg238Pro (c.713G>C) pathogenic?

PGAP2 p.Arg238Pro (c.713G>C) is classified Pathogenic/Likely pathogenic in PGAP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-07-08). AlphaMissense: likely pathogenic (0.915); Ultra-rare (popmax 0.022%, sas); Associated with hyperphosphatasia with intellectual disability syndrome 3.

What condition is associated with PGAP2 p.Arg238Pro (c.713G>C)?

PGAP2 p.Arg238Pro (c.713G>C) is associated with hyperphosphatasia with intellectual disability syndrome 3, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3 (ClinVar).

How common is PGAP2 p.Arg238Pro (c.713G>C) in the general population?

PGAP2 p.Arg238Pro (c.713G>C) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about PGAP2 p.Arg238Pro (c.713G>C)?

AlphaMissense predicts likely pathogenic (score 0.915) — an in-silico prediction, not a clinical call.

PGAP2 p.Arg238Pro

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.713G>C · rs774843232 · VCV50503

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.915 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphosphatasia with intellectual disability syndrome 3

Computational evidence

Protein change
AlphaMissense	0.915	likely pathogenic ✓ concordant with ClinVar
REVEL	0.217	benign-leaning
SaProt	LLR -13.17	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.82, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.023 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R177P vs ClinVar R238P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.022% South Asian · 20/91,078 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00149% 24/1,614,024 alleles · ultra-rare exomes 23/1,461,842 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.022%	4,554
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000254%	393,338

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.Arg238Pro
Coding: c.713G>C
MANE Select: NM_014489
dbSNP: rs774843232
Type: single nucleotide variant
Location: chr11:3825024 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00
Residue 177 UniProt numbering: a UniProt-annotated variant site (in hpmrs3; does not affect protein expression; decreases gpi anchor biosynthetic process)

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

Also linked: cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3

For Hyperphosphatasia-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PGAP2 p.Arg238Cys Uncertain significance ★★ ⚠ same residue
PGAP2 p.Ala127Val 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-arg238pro (accessed [today's date]).

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