Is INPP5E p.Phe425Leu (c.1275C>G) pathogenic?

INPP5E p.Phe425Leu (c.1275C>G) is classified Uncertain significance in INPP5E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-07-31). AlphaMissense: likely pathogenic (0.9402); Very rare (popmax 0.00136%, nfe); Associated with Joubert syndrome.

What condition is associated with INPP5E p.Phe425Leu (c.1275C>G)?

INPP5E p.Phe425Leu (c.1275C>G) is associated with Joubert syndrome (ClinVar).

How common is INPP5E p.Phe425Leu (c.1275C>G) in the general population?

INPP5E p.Phe425Leu (c.1275C>G) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about INPP5E p.Phe425Leu (c.1275C>G)?

AlphaMissense predicts likely pathogenic (score 0.9402) — an in-silico prediction, not a clinical call.

INPP5E p.Phe425Leu

c.1275C>G · rs780525765 · VCV958797

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9402 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.9402	likely pathogenic
REVEL	0.713	pathogenic-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.77, phastCons 1
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,668 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0011% 16/1,460,638 alleles · very rare

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.Phe425Leu
Coding: c.1275C>G
MANE Select: NM_019892
dbSNP: rs780525765
Type: single nucleotide variant
Location: chr9:136432960 (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.Phe425= 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-phe425leu (accessed [today's date]).

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