Is INPP5E p.Pro577Arg (c.1730C>G) pathogenic?

INPP5E p.Pro577Arg (c.1730C>G) is classified Conflicting classifications of pathogenicity in INPP5E (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0945); Ultra-rare (popmax 0.0717%, nfe); Associated with Joubert syndrome.

What condition is associated with INPP5E p.Pro577Arg (c.1730C>G)?

INPP5E p.Pro577Arg (c.1730C>G) is associated with Joubert syndrome, optic atrophy, Joubert syndrome 1 (ClinVar).

How common is INPP5E p.Pro577Arg (c.1730C>G) in the general population?

INPP5E p.Pro577Arg (c.1730C>G) is ultra-rare (popmax 0.0717%, nfe) (gnomAD).

What do computational predictors say about INPP5E p.Pro577Arg (c.1730C>G)?

AlphaMissense predicts likely benign (score 0.0945) — an in-silico prediction, not a clinical call.

INPP5E p.Pro577Arg

c.1730C>G · rs147967974 · VCV365879

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0945 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0717%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.0945	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.98, phastCons 0.97
Overall
CADD	18.17	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 0.0717% European (non-Finnish) · 823/1,148,230 alleles

Filtering AF 0.0676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0659%

Overall 0.234% 3,632/1,554,530 alleles · ultra-rare exomes 3,059/1,402,220 · genomes 573/152,310 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	4.36%	23
Remaining individualsnot grpmax-eligible	0.234%	427
Ashkenazi Jewishnot grpmax-eligible	0.185%	541
European (non-Finnish)grpmax	0.0717%	1,395
Admixed American	0.00587%	17,043
African / African-American	0.00136%	73,506

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro577Arg
Coding: c.1730C>G
MANE Select: NM_019892
dbSNP: rs147967974
Type: single nucleotide variant
Location: chr9:136430349 (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: optic atrophy Joubert syndrome 1

Similar variants

INPP5E p.Pro577= Likely benign ★★ same residue
INPP5E p.Pro577Ser 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

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-pro577arg (accessed [today's date]).

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