Is INPP5E p.Pro586= (c.1758T>C) pathogenic?

INPP5E p.Pro586= (c.1758T>C) is classified Likely benign in INPP5E (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-23). Very rare (popmax 0.00584%, nfe); Associated with MORM syndrome.

What condition is associated with INPP5E p.Pro586= (c.1758T>C)?

INPP5E p.Pro586= (c.1758T>C) is associated with MORM syndrome, Joubert syndrome 1, Joubert syndrome (ClinVar).

How common is INPP5E p.Pro586= (c.1758T>C) in the general population?

INPP5E p.Pro586= (c.1758T>C) is very rare (popmax 0.00584%, nfe) (gnomAD).

How is MORM syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

INPP5E p.Pro586=

c.1758T>C · rs1222127887 · VCV1125526

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00584%, nfe)

Conditions

MORM 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 -3.7	GERP -3.3
Overall
CADD	0.347	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00584% European (non-Finnish) · 67/1,147,186 alleles

Filtering AF 0.00466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00429%

Overall 0.00438% 68/1,552,044 alleles · very rare exomes 63/1,399,840 · genomes 5/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00584%	17,122
Admixed American	0.00196%	50,996

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.Pro586=
Coding: c.1758T>C
MANE Select: NM_019892
dbSNP: rs1222127887
Type: single nucleotide variant
Location: chr9:136430321 (GRCh38)
Structure: AlphaFold pLDDT 88.46

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

Disease context

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

Also linked: Joubert syndrome 1 Joubert syndrome

For MORM syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

INPP5E p.Pro586Leu 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-pro586 (accessed [today's date]).

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