Is INPP5E p.Pro32Arg (c.95C>G) pathogenic?

INPP5E p.Pro32Arg (c.95C>G) is classified Uncertain significance in INPP5E (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-29). AlphaMissense: likely benign (0.0648); Ultra-rare (popmax 0.0111%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INPP5E p.Pro32Arg (c.95C>G)?

INPP5E p.Pro32Arg (c.95C>G) is associated with Inborn genetic diseases, Joubert syndrome 1, MORM syndrome (ClinVar).

How common is INPP5E p.Pro32Arg (c.95C>G) in the general population?

INPP5E p.Pro32Arg (c.95C>G) is ultra-rare (popmax 0.0111%, nfe) (gnomAD).

What do computational predictors say about INPP5E p.Pro32Arg (c.95C>G)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

INPP5E p.Pro32Arg

c.95C>G · rs1018506310 · VCV1000799

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.048	GERP -1.8
Overall
CADD	0.823	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% European (non-Finnish) · 121/1,091,028 alleles

Filtering AF 0.00947% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00887%

Overall 0.00909% 128/1,408,554 alleles · ultra-rare exomes 117/1,256,516 · genomes 11/152,038 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0111%	9,017
African / African-American	0.00606%	16,490
Remaining individualsnot grpmax-eligible	0.00555%	18,012

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.Pro32Arg
Coding: c.95C>G
MANE Select: NM_019892
dbSNP: rs1018506310
Type: single nucleotide variant
Location: chr9:136439325 (GRCh38)
Structure: AlphaFold pLDDT 88.46

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 1 MORM syndrome Joubert syndrome

Similar variants

INPP5E p.Pro32Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro32arg (accessed [today's date]).

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