Is PGAP3 p.Pro105Arg (c.314C>G) pathogenic?

PGAP3 p.Pro105Arg (c.314C>G) is classified Pathogenic in PGAP3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-02-06). AlphaMissense: likely pathogenic (0.9639); Absent from gnomAD v4.1; Associated with hyperphosphatasia with intellectual disability syndrome 4.

What condition is associated with PGAP3 p.Pro105Arg (c.314C>G)?

PGAP3 p.Pro105Arg (c.314C>G) is associated with hyperphosphatasia with intellectual disability syndrome 4 (ClinVar).

How common is PGAP3 p.Pro105Arg (c.314C>G) in the general population?

PGAP3 p.Pro105Arg (c.314C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PGAP3 p.Pro105Arg (c.314C>G)?

AlphaMissense predicts likely pathogenic (score 0.9639) — an in-silico prediction, not a clinical call.

PGAP3 p.Pro105Arg

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.314C>G · rs371549948 · VCV125440

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9639 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphosphatasia with intellectual disability syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9639	likely pathogenic ✓ concordant with ClinVar · top 9% in PGAP3
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -14.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.63 · regional, not allelic
Overall
CADD	29.8	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: PGAP3
Protein: p.Pro105Arg
Coding: c.314C>G
MANE Select: NM_033419
dbSNP: rs371549948
Type: single nucleotide variant
Location: chr17:39684715 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.17
Residue 105: a UniProt-annotated variant site (in hpmrs4; results in partial functional impairment; the mutant does not localize to the golgi apparatus but is retained in the endoplasmic reticulum)

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.Pro105Gln Likely pathogenic ★★ same residue
PGAP3 p.Pro105Leu Uncertain significance ★ ⚠ same residue
PGAP3 p.Pro105= 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

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-pro105arg (accessed [today's date]).

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