Is INPP5E p.Ala56Pro (c.166G>C) pathogenic?

INPP5E p.Ala56Pro (c.166G>C) is classified Uncertain significance in INPP5E (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-06). AlphaMissense: likely benign (0.0802); Very rare (popmax 0.00124%, sas); Associated with Joubert syndrome.

What condition is associated with INPP5E p.Ala56Pro (c.166G>C)?

INPP5E p.Ala56Pro (c.166G>C) is associated with Joubert syndrome (ClinVar).

How common is INPP5E p.Ala56Pro (c.166G>C) in the general population?

INPP5E p.Ala56Pro (c.166G>C) is very rare (popmax 0.00124%, sas) (gnomAD).

What do computational predictors say about INPP5E p.Ala56Pro (c.166G>C)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

INPP5E p.Ala56Pro

c.166G>C · rs987360153 · VCV1504508

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00124%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.31, phastCons 0.015
Overall
CADD	19.89	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

Grpmax group 0.00124% South Asian · 1/80,868 alleles

Overall 6.62e-05% 1/1,510,682 alleles · very rare exomes 1/1,358,464 · genomes 0/152,218 · joint denominator

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.Ala56Pro
Coding: c.166G>C
MANE Select: NM_019892
dbSNP: rs987360153
Type: single nucleotide variant
Location: chr9:136439254 (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.Ala56= Likely benign ★ same residue
INPP5E p.Ala56fs Pathogenic ★ 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

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-ala56pro (accessed [today's date]).

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