Is PGAP1 p.Ile465fs (c.1394_1397del) pathogenic?

PGAP1 p.Ile465fs (c.13941397del) is classified Pathogenic in PGAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). Very rare (popmax 0.00684%, amr); Associated with intellectual disability, autosomal recessive 42.

What condition is associated with PGAP1 p.Ile465fs (c.1394_1397del)?

PGAP1 p.Ile465fs (c.1394_1397del) is associated with intellectual disability, autosomal recessive 42 (ClinVar).

How common is PGAP1 p.Ile465fs (c.1394_1397del) in the general population?

PGAP1 p.Ile465fs (c.1394_1397del) is very rare (popmax 0.00684%, amr) (gnomAD).

PGAP1 p.Ile465fs

c.1394_1397del · rs781325598 · VCV474988

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00684%, amr)

Conditions

intellectual disability, autosomal recessive 42

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.3	GERP -0.7
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00684% Admixed American · 4/58,472 alleles

Filtering AF 0.0023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.000389% 6/1,542,214 alleles · very rare exomes 3/1,389,958 · genomes 3/152,256 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00684%	14,618
European (non-Finnish)	0.000179%	559,488

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.Ile465fs
Coding: c.1394_1397del
MANE Select: NM_024989
dbSNP: rs781325598
Type: Microsatellite
Location: chr2:196875775 (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

PGAP1 p.Leu197del Pathogenic/Likely pathogenic ★★ same condition
PGAP1 c.808-7_808-3del Conflicting classifications of pathogenicity ★ same condition
PGAP1 c.1174-20_1174-16del Likely benign ★ same condition
PGAP1 c.861-14_861-11del Benign ★ same condition
PGAP1 p.Arg786fs Pathogenic ★★ same condition
PGAP1 p.Gln466Ter Pathogenic ★★ same condition
PGAP1 p.Gln555Ter Pathogenic/Likely pathogenic ★★ same condition
PGAP1 p.Leu681fs 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/pgap1-p-ile465fs (accessed [today's date]).

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