Is PGAP2 p.Thr49Ile (c.146C>T) pathogenic?

PGAP2 p.Thr49Ile (c.146C>T) is classified Conflicting classifications of pathogenicity in PGAP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-23). AlphaMissense: likely pathogenic (0.8606); Absent from gnomAD v4.1; Associated with hyperphosphatasia with intellectual disability syndrome 3.

What condition is associated with PGAP2 p.Thr49Ile (c.146C>T)?

PGAP2 p.Thr49Ile (c.146C>T) is associated with hyperphosphatasia with intellectual disability syndrome 3 (ClinVar).

How common is PGAP2 p.Thr49Ile (c.146C>T) in the general population?

PGAP2 p.Thr49Ile (c.146C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PGAP2 p.Thr49Ile (c.146C>T)?

AlphaMissense predicts likely pathogenic (score 0.8606) — an in-silico prediction, not a clinical call.

PGAP2 p.Thr49Ile

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.146C>T · rs2495380745 · VCV2235024

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8606 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphosphatasia with intellectual disability syndrome 3

Computational evidence

Protein change
AlphaMissense	0.8606	likely pathogenic
REVEL	0.244	benign-leaning
SaProt	LLR -11.99	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 161 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	27.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PGAP2
Protein: p.Thr49Ile
Coding: c.146C>T
MANE Select: NM_014489
dbSNP: rs2495380745
Type: single nucleotide variant
Location: chr11:3811405 (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.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
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-thr49ile (accessed [today's date]).

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