Is INPP5E p.Pro453= (c.1359C>T) pathogenic?

INPP5E p.Pro453= (c.1359C>T) is classified Benign in INPP5E (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 11.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Joubert syndrome 1.

What condition is associated with INPP5E p.Pro453= (c.1359C>T)?

INPP5E p.Pro453= (c.1359C>T) is associated with Joubert syndrome 1, Joubert syndrome (ClinVar).

INPP5E p.Pro453=

Q: How common is INPP5E p.Pro453= (c.1359C>T) in the general population?

INPP5E p.Pro453= (c.1359C>T) is common (popmax 11.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1359C>T · rs35774078 · VCV129267

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 11.5%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Joubert syndrome 1

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 -11	GERP -3.3
Overall
CADD	0.246	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.5% African / African-American · 8,430/73,242 alleles

Filtering AF 11.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.2%

Overall 3.13% 48,554/1,550,870 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.5%	9
Ashkenazi Jewishnot grpmax-eligible	11%	9
Middle Eastern	9.87%	10
Remaining individualsnot grpmax-eligible	4.42%	23
Admixed American	3.83%	26
Amishnot grpmax-eligible	2.85%	35
European (non-Finnish)	2.66%	38
South Asian	0.942%	106
Finnishnot grpmax-eligible	0.516%	194
East Asian	0.473%	212

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.Pro453=
Coding: c.1359C>T
MANE Select: NM_015160 · reported on NM_019892
dbSNP: rs35774078
Type: single nucleotide variant
Location: chr9:136432507 (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

PMPCA p.Val453Met 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.Arg563His 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-pro453 (accessed [today's date]).

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