Is PGAP1 p.Gly499Glu (c.1496G>A) pathogenic?

PGAP1 p.Gly499Glu (c.1496G>A) is classified Uncertain significance in PGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-08). AlphaMissense: likely benign (0.1637); Ultra-rare (popmax 0.0199%, nfe); Associated with intellectual disability, autosomal recessive 42.

What condition is associated with PGAP1 p.Gly499Glu (c.1496G>A)?

PGAP1 p.Gly499Glu (c.1496G>A) is associated with intellectual disability, autosomal recessive 42 (ClinVar).

How common is PGAP1 p.Gly499Glu (c.1496G>A) in the general population?

PGAP1 p.Gly499Glu (c.1496G>A) is ultra-rare (popmax 0.0199%, nfe) (gnomAD).

What do computational predictors say about PGAP1 p.Gly499Glu (c.1496G>A)?

AlphaMissense predicts likely benign (score 0.1637) — an in-silico prediction, not a clinical call.

PGAP1 p.Gly499Glu

c.1496G>A · rs201928408 · VCV2420875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1637 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0199%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

intellectual disability, autosomal recessive 42

Computational evidence

Protein change
AlphaMissense	0.1637	likely benign
REVEL	0.397	indeterminate
SaProt	LLR -4.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	17.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0199% European (non-Finnish) · 234/1,176,796 alleles

Filtering AF 0.0178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.017%

Overall 0.0148% 239/1,610,056 alleles · ultra-rare exomes 231/1,458,058 · genomes 8/151,998 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0199%	5,029
Remaining individualsnot grpmax-eligible	0.00481%	20,784
African / African-American	0.00267%	37,403

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: PGAP1
Protein: p.Gly499Glu
Coding: c.1496G>A
MANE Select: NM_024989
dbSNP: rs201928408
Type: single nucleotide variant
Location: chr2:196873689 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 89.15

Full PGAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal recessive 42 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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PGAP1 p.Ala298Thr Uncertain significance ★★ ⚠ same condition
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PGAP1 p.Arg231Gln Uncertain significance ★★ ⚠ same condition
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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/pgap1-p-gly499glu (accessed [today's date]).

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