Is INPP5E p.Pro15fs (c.44del) pathogenic?

INPP5E p.Pro15fs (c.44del) is classified Pathogenic in INPP5E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-03). Very rare (popmax 0.00027%, nfe); Associated with Joubert syndrome.

What condition is associated with INPP5E p.Pro15fs (c.44del)?

INPP5E p.Pro15fs (c.44del) is associated with Joubert syndrome (ClinVar).

How common is INPP5E p.Pro15fs (c.44del) in the general population?

INPP5E p.Pro15fs (c.44del) is very rare (popmax 0.00027%, nfe) (gnomAD).

INPP5E p.Pro15fs

c.44del · rs1332623576 · VCV817662

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00027%, nfe)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.4	GERP -1.6

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00027% European (non-Finnish) · 3/1,111,128 alleles

Filtering AF 7.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000274% 4/1,457,668 alleles · very rare exomes 4/1,305,538 · genomes 0/152,130 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00178%	56,210
European (non-Finnish)grpmax	0.00027%	370,376

Remaining individuals 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: INPP5E
Protein: p.Pro15fs
Coding: c.44del
MANE Select: NM_019892
dbSNP: rs1332623576
Type: Deletion
Location: chr9:136439376 (GRCh38)
Structure: AlphaFold pLDDT 88.46

Full INPP5E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INPP5E p.Pro15Leu Uncertain significance ★ ⚠ same residue
INPP5E p.Gly158fs Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Met1_Ser3del Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Val587fs Pathogenic/Likely pathogenic ★★ same condition
INPP5E c.1159+16_1159+33del Uncertain significance ★★ same condition
INPP5E p.Lys312del Uncertain significance ★★ same condition
INPP5E c.1549+17del Benign/Likely benign ★★ same condition
INPP5E c.812+2_812+5del 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/inpp5e-p-pro15fs (accessed [today's date]).

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