Is INPP5E p.Ser582= (c.1746C>T) pathogenic?

INPP5E p.Ser582= (c.1746C>T) is classified Likely benign in INPP5E (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-26). Ultra-rare (popmax 0.0166%, mid); Associated with Joubert syndrome.

What condition is associated with INPP5E p.Ser582= (c.1746C>T)?

INPP5E p.Ser582= (c.1746C>T) is associated with Joubert syndrome (ClinVar).

How common is INPP5E p.Ser582= (c.1746C>T) in the general population?

INPP5E p.Ser582= (c.1746C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

INPP5E p.Ser582=

c.1746C>T · rs888901624 · VCV1594337

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, 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 -9	GERP -3.3
Overall
CADD	0.497	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,016 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00486%

Overall 0.00155% 24/1,552,692 alleles · ultra-rare exomes 22/1,400,466 · genomes 2/152,226 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,016
South Asian	0.0119%	8,414
African / African-American	0.00683%	14,641
East Asian	0.00242%	41,262
Remaining individualsnot grpmax-eligible	0.00166%	60,166
European (non-Finnish)	0.000523%	191,241

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.Ser582=
Coding: c.1746C>T
MANE Select: NM_019892
dbSNP: rs888901624
Type: single nucleotide variant
Location: chr9:136430333 (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.Ser582Cys 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-ser582 (accessed [today's date]).

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