Is INPP5E p.Phe425= (c.1275C>T) pathogenic?

INPP5E p.Phe425= (c.1275C>T) is classified Likely benign in INPP5E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-09). Ultra-rare (popmax 0.0493%, mid); Associated with Joubert syndrome.

What condition is associated with INPP5E p.Phe425= (c.1275C>T)?

INPP5E p.Phe425= (c.1275C>T) is associated with Joubert syndrome (ClinVar).

How common is INPP5E p.Phe425= (c.1275C>T) in the general population?

INPP5E p.Phe425= (c.1275C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

INPP5E p.Phe425=

c.1275C>T · rs780525765 · VCV697350

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
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	10.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,082 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.0062% 100/1,612,884 alleles · ultra-rare exomes 92/1,460,638 · genomes 8/152,246 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.329%	304
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,972
Middle Easterngrpmax	0.0493%	2,027
South Asian	0.022%	4,547
Remaining individualsnot grpmax-eligible	0.0112%	8,923
European (non-Finnish)	0.00441%	22,686

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe425=
Coding: c.1275C>T
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.Phe425Leu Uncertain significance ★★ ⚠ 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-phe425 (accessed [today's date]).

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