Is INPP5E p.Arg486His (c.1457G>A) pathogenic?

INPP5E p.Arg486His (c.1457G>A) is classified Conflicting classifications of pathogenicity in INPP5E (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-06-03). AlphaMissense: ambiguous (0.5405); Ultra-rare (popmax 0.0358%, eas); Associated with Joubert syndrome.

What condition is associated with INPP5E p.Arg486His (c.1457G>A)?

INPP5E p.Arg486His (c.1457G>A) is associated with Joubert syndrome, inherited retinal dystrophy (ClinVar).

How common is INPP5E p.Arg486His (c.1457G>A) in the general population?

INPP5E p.Arg486His (c.1457G>A) is ultra-rare (popmax 0.0358%, eas) (gnomAD).

What do computational predictors say about INPP5E p.Arg486His (c.1457G>A)?

AlphaMissense predicts ambiguous (score 0.5405) — an in-silico prediction, not a clinical call.

INPP5E p.Arg486His

c.1457G>A · rs367592401 · VCV1696366

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5405 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0358%, eas)

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.5405	ambiguous
REVEL	0.605	indeterminate
SaProt	LLR -12.68	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 1.5, phastCons 1
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0358% East Asian · 16/44,754 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0105% 170/1,611,606 alleles · ultra-rare exomes 155/1,460,262 · genomes 15/151,344 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0358%	2,797
Remaining individualsnot grpmax-eligible	0.0192%	5,205
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0111%	9,005
Admixed American	0.00668%	14,978
Finnishnot grpmax-eligible	0.00319%	31,307
African / African-American	0.00268%	37,328
South Asian	0.0022%	45,495

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.Arg486His
Coding: c.1457G>A
MANE Select: NM_019892
dbSNP: rs367592401
Type: single nucleotide variant
Location: chr9:136431916 (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

Also linked: inherited retinal dystrophy

Similar variants

INPP5E p.Arg486Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
INPP5E p.Arg486Ser 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

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-arg486his (accessed [today's date]).

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