Is PGAP1 p.Leu681fs (c.2042del) pathogenic?

PGAP1 p.Leu681fs (c.2042del) is classified Pathogenic/Likely pathogenic in PGAP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-18). Very rare (popmax 0.00167%, amr); Associated with intellectual disability, autosomal recessive 42.

What condition is associated with PGAP1 p.Leu681fs (c.2042del)?

PGAP1 p.Leu681fs (c.2042del) is associated with intellectual disability, autosomal recessive 42 (ClinVar).

How common is PGAP1 p.Leu681fs (c.2042del) in the general population?

PGAP1 p.Leu681fs (c.2042del) is very rare (popmax 0.00167%, amr) (gnomAD).

PGAP1 p.Leu681fs

c.2042del · rs756609752 · VCV983046

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, 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 22 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.89	GERP -2.7
Overall
CADD	33.0	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 0.00167% Admixed American · 1/59,998 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00174% 28/1,613,356 alleles · very rare exomes 22/1,461,132 · genomes 6/152,224 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0541%	1,849
Finnishnot grpmax-eligible	0.00469%	21,306
Remaining individualsnot grpmax-eligible	0.0032%	31,245
Admixed Americangrpmax	0.00167%	59,998
European (non-Finnish)	0.000509%	196,586

Ashkenazi Jewish 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: PGAP1
Protein: p.Leu681fs
Coding: c.2042del
MANE Select: NM_024989
dbSNP: rs756609752
Type: Deletion
Location: chr2:196847111 (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 c.1426+1del Likely pathogenic ★ same condition
PGAP1 p.Asn7fs Pathogenic ★ same condition
PGAP1 p.Cys623fs Pathogenic ★ same condition
PGAP1 p.Lys308fs Pathogenic ★ same condition
PGAP1 p.Pro92del Pathogenic ★ same condition
PGAP1 p.Pro92fs Pathogenic ★ same condition
PGAP1 p.Ser97fs Likely pathogenic ★ same condition
PGAP1 p.Val516fs 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-leu681fs (accessed [today's date]).

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