Is PGAP3 p.Pro276Leu (c.827C>T) pathogenic?

PGAP3 p.Pro276Leu (c.827C>T) is classified Pathogenic/Likely pathogenic in PGAP3 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.9295); Very rare (popmax 0.00586%, nfe); Associated with hyperphosphatasia with intellectual disability syndrome 4.

What condition is associated with PGAP3 p.Pro276Leu (c.827C>T)?

PGAP3 p.Pro276Leu (c.827C>T) is associated with hyperphosphatasia with intellectual disability syndrome 4 (ClinVar).

How common is PGAP3 p.Pro276Leu (c.827C>T) in the general population?

PGAP3 p.Pro276Leu (c.827C>T) is very rare (popmax 0.00586%, nfe) (gnomAD).

What do computational predictors say about PGAP3 p.Pro276Leu (c.827C>T)?

AlphaMissense predicts likely pathogenic (score 0.9295) — an in-silico prediction, not a clinical call.

PGAP3 p.Pro276Leu

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.827C>T · rs750093817 · VCV426134

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9295 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00586%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphosphatasia with intellectual disability syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9295	likely pathogenic ✓ concordant with ClinVar
REVEL	0.669	pathogenic-leaning
SaProt	LLR -15.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.63 · regional, not allelic
Overall
CADD	29.3	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 0.00586% European (non-Finnish) · 69/1,177,478 alleles

Filtering AF 0.00471% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00523% 84/1,607,474 alleles · very rare exomes 75/1,455,322 · genomes 9/152,152 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0126%	7,948
Remaining individualsnot grpmax-eligible	0.00642%	15,573
European (non-Finnish)grpmax	0.00586%	17,065
East Asian	0.00224%	44,658
Admixed American	0.0017%	58,722
South Asian	0.00112%	89,516

Finnish 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: PGAP3
Protein: p.Pro276Leu
Coding: c.827C>T
MANE Select: NM_033419
dbSNP: rs750093817
Type: single nucleotide variant
Location: chr17:39673123 (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 p.Pro276= Likely benign ★ same residue
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

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-pro276leu (accessed [today's date]).

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