Is PGAP2 p.Arg246Gln (c.737G>A) pathogenic?

PGAP2 p.Arg246Gln (c.737G>A) is classified Likely pathogenic in PGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely benign (0.1617); Very rare (popmax 0.00167%, amr); Associated with hyperphosphatasia with intellectual disability syndrome 3.

What condition is associated with PGAP2 p.Arg246Gln (c.737G>A)?

PGAP2 p.Arg246Gln (c.737G>A) is associated with hyperphosphatasia with intellectual disability syndrome 3 (ClinVar).

How common is PGAP2 p.Arg246Gln (c.737G>A) in the general population?

PGAP2 p.Arg246Gln (c.737G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PGAP2 p.Arg246Gln (c.737G>A)?

AlphaMissense predicts likely benign (score 0.1617) — an in-silico prediction, not a clinical call.

PGAP2 p.Arg246Gln

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.737G>A · VCV4849327

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphosphatasia with intellectual disability syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1617	likely benign ⚠ discordant with ClinVar
REVEL	0.191	benign-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.023 · regional, not allelic
Overall
CADD	25.8	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 R185Q vs ClinVar R246Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,012 alleles

Overall 0.000186% 3/1,614,144 alleles · very rare exomes 3/1,461,876 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Admixed Americangrpmax	0.00167%	60,012
European (non-Finnish)	8.47e-05%	1,180,020

Ashkenazi Jewish 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.Arg246Gln
Coding: c.737G>A
MANE Select: NM_014489
Type: single nucleotide variant
Location: chr11:3825048 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00

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.Arg246Leu Likely pathogenic ★ ⚠ same residue
PGAP2 p.Arg246Trp 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

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-arg246gln (accessed [today's date]).

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