Is INPP5E p.Pro28Ala (c.82C>G) pathogenic?

INPP5E p.Pro28Ala (c.82C>G) is classified Uncertain significance in INPP5E (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-07). AlphaMissense: likely benign (0.0607); Absent from gnomAD v4.1; Associated with Joubert syndrome.

What condition is associated with INPP5E p.Pro28Ala (c.82C>G)?

INPP5E p.Pro28Ala (c.82C>G) is associated with Joubert syndrome (ClinVar).

How common is INPP5E p.Pro28Ala (c.82C>G) in the general population?

INPP5E p.Pro28Ala (c.82C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about INPP5E p.Pro28Ala (c.82C>G)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

INPP5E p.Pro28Ala

c.82C>G · rs2538895984 · VCV2185692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.91, phastCons 0.44
Overall
CADD	12.86	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: INPP5E
Protein: p.Pro28Ala
Coding: c.82C>G
MANE Select: NM_019892
dbSNP: rs2538895984
Type: single nucleotide variant
Location: chr9:136439338 (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.Pro28= Likely benign ★ same residue
INPP5E p.Arg378Cys Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg435Gln Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg435Trp Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg557His Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg585Cys Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg621Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
INPP5E p.Arg621Trp 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/inpp5e-p-pro28ala (accessed [today's date]).

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