Is PGAP2 p.Ala127Val (c.380C>T) pathogenic?

PGAP2 p.Ala127Val (c.380C>T) is classified Likely pathogenic in PGAP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-01). AlphaMissense: likely pathogenic (0.8714); Very rare (popmax 0.00167%, amr); Associated with hyperphosphatasia with intellectual disability syndrome 3.

What condition is associated with PGAP2 p.Ala127Val (c.380C>T)?

PGAP2 p.Ala127Val (c.380C>T) is associated with hyperphosphatasia with intellectual disability syndrome 3 (ClinVar).

How common is PGAP2 p.Ala127Val (c.380C>T) in the general population?

PGAP2 p.Ala127Val (c.380C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PGAP2 p.Ala127Val (c.380C>T)?

AlphaMissense predicts likely pathogenic (score 0.8714) — an in-silico prediction, not a clinical call.

PGAP2 p.Ala127Val

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.380C>T · rs752346360 · VCV633511

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphosphatasia with intellectual disability syndrome 3

Computational evidence

Protein change
AlphaMissense	0.8714	likely pathogenic ✓ concordant with ClinVar
REVEL	0.705	pathogenic-leaning
SaProt	LLR -10.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.023 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A66V vs ClinVar A127V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,002 alleles

Overall 6.23e-05% 1/1,605,304 alleles · very rare exomes 1/1,453,058 · genomes 0/152,246 · joint denominator

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.Ala127Val
Coding: c.380C>T
MANE Select: NM_014489
dbSNP: rs752346360
Type: single nucleotide variant
Location: chr11:3823914 (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.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
PGAP2 p.Arg246Leu 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-ala127val (accessed [today's date]).

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