Is PGAP1 p.Glu546= (c.1638A>G) pathogenic?

PGAP1 p.Glu546= (c.1638A>G) is classified Conflicting classifications of pathogenicity in PGAP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-15). Ultra-rare (popmax 0.0328%, nfe); Associated with intellectual disability, autosomal recessive 42.

How common is PGAP1 p.Glu546= (c.1638A>G) in the general population?

PGAP1 p.Glu546= (c.1638A>G) is ultra-rare (popmax 0.0328%, nfe) (gnomAD).

PGAP1 p.Glu546=

Q: What condition is associated with PGAP1 p.Glu546= (c.1638A>G)?

PGAP1 p.Glu546= (c.1638A>G) is associated with intellectual disability, autosomal recessive 42, hereditary spastic paraplegia (ClinVar).

c.1638A>G · rs142482606 · VCV1344447

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0328%, nfe)

Conditions

intellectual disability, autosomal recessive 42

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP 1.5, phastCons 1
Overall
CADD	8.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0328% European (non-Finnish) · 386/1,178,100 alleles

Filtering AF 0.0301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.029%

Overall 0.0251% 404/1,611,916 alleles · ultra-rare exomes 385/1,459,642 · genomes 19/152,274 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0328%	3,052
Remaining individualsnot grpmax-eligible	0.0112%	8,918
Admixed American	0.00834%	11,996
African / African-American	0.00667%	14,998
South Asian	0.0011%	91,004

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.Glu546=
Coding: c.1638A>G
MANE Select: NM_024989
dbSNP: rs142482606
Type: single nucleotide variant
Location: chr2:196872531 (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

Also linked: hereditary spastic paraplegia

Similar variants

PGAP1 p.Gln466Ter Pathogenic ★★ same condition
PGAP1 p.Gln555Ter Pathogenic/Likely pathogenic ★★ same condition
PGAP1 p.Tyr758Ter Pathogenic/Likely pathogenic ★★ same condition
PGAP1 p.Ala298Thr Uncertain significance ★★ ⚠ same condition
PGAP1 p.Ala714Val Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg231Gln Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg250His Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg803Cys Uncertain significance ★★ ⚠ 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/pgap1-p-glu546 (accessed [today's date]).

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