Is INPP5E p.Ala463= (c.1389G>A) pathogenic?

INPP5E p.Ala463= (c.1389G>A) is classified Uncertain significance in INPP5E (ClinVar, Single submitter, 2 submitters; last evaluated 2023-12-22). Very rare (popmax 0.00401%, afr); Associated with Joubert syndrome.

What condition is associated with INPP5E p.Ala463= (c.1389G>A)?

INPP5E p.Ala463= (c.1389G>A) is associated with Joubert syndrome (ClinVar).

How common is INPP5E p.Ala463= (c.1389G>A) in the general population?

INPP5E p.Ala463= (c.1389G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

INPP5E p.Ala463=

c.1389G>A · rs779735920 · VCV1364358

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.97	acceptor gain · deltas
Pangolin	Δ0.67	gain · loss 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.65	GERP -2.9, phastCons 0.007
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,850 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00267% 43/1,612,470 alleles · very rare exomes 37/1,460,482 · genomes 6/151,988 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,950
Admixed American	0.00333%	29,999
European (non-Finnish)	0.00305%	32,775
East Asian	0.00223%	44,832
South Asian	0.0011%	91,074

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.Ala463=
Coding: c.1389G>A
MANE Select: NM_019892
dbSNP: rs779735920
Type: single nucleotide variant
Location: chr9:136431984 (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.Ala463Val Uncertain significance ★★ ⚠ same residue
PMPCA p.His463= 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

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-ala463 (accessed [today's date]).

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