Is INPP5E p.Phe469= (c.1407C>T) pathogenic?

INPP5E p.Phe469= (c.1407C>T) is classified Conflicting classifications of pathogenicity in INPP5E (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-08). Ultra-rare (popmax 0.0164%, mid); Associated with Joubert syndrome 1.

What condition is associated with INPP5E p.Phe469= (c.1407C>T)?

INPP5E p.Phe469= (c.1407C>T) is associated with Joubert syndrome 1, Joubert syndrome (ClinVar).

How common is INPP5E p.Phe469= (c.1407C>T) in the general population?

INPP5E p.Phe469= (c.1407C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

INPP5E p.Phe469=

c.1407C>T · rs377483407 · VCV365881

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Joubert syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -3.3	GERP -3
Overall
CADD	11.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000806% 13/1,612,318 alleles · ultra-rare exomes 10/1,460,486 · genomes 3/151,832 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0032%	31,226
Finnishnot grpmax-eligible	0.00319%	31,385
African / African-American	0.00267%	37,407
European (non-Finnish)	0.000509%	196,644

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.Phe469=
Coding: c.1407C>T
MANE Select: NM_019892
dbSNP: rs377483407
Type: single nucleotide variant
Location: chr9:136431966 (GRCh38)
Structure: AlphaFold pLDDT 88.46

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

Disease context

Joubert syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome

Similar variants

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.Arg563His 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-phe469 (accessed [today's date]).

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