Is INPP5E p.Val558Phe (c.1672G>T) pathogenic?

INPP5E p.Val558Phe (c.1672G>T) is classified Likely pathogenic in INPP5E (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-20). AlphaMissense: likely pathogenic (0.847); Very rare (popmax 8.7e-05%, nfe); Associated with INPP5E-related disorder.

What condition is associated with INPP5E p.Val558Phe (c.1672G>T)?

INPP5E p.Val558Phe (c.1672G>T) is associated with INPP5E-related disorder (ClinVar).

How common is INPP5E p.Val558Phe (c.1672G>T) in the general population?

INPP5E p.Val558Phe (c.1672G>T) is very rare (popmax 8.7e-05%, nfe) (gnomAD).

What do computational predictors say about INPP5E p.Val558Phe (c.1672G>T)?

AlphaMissense predicts likely pathogenic (score 0.847) — an in-silico prediction, not a clinical call.

INPP5E p.Val558Phe

c.1672G>T · rs1417022247 · VCV866732

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.7e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

INPP5E-related disorder

Computational evidence

Protein change
AlphaMissense	0.847	likely pathogenic ✓ concordant with ClinVar
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -10.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.34	GERP 0.14, phastCons 0.023
Overall
CADD	24.3	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 8.7e-05% European (non-Finnish) · 1/1,148,862 alleles

Overall 6.43e-05% 1/1,555,748 alleles · very rare exomes 1/1,403,376 · genomes 0/152,372 · joint denominator

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.Val558Phe
Coding: c.1672G>T
MANE Select: NM_019892
dbSNP: rs1417022247
Type: single nucleotide variant
Location: chr9:136430407 (GRCh38)
Structure: AlphaFold pLDDT 88.46

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

Disease context

INPP5E-related disorder

Similar variants

INPP5E p.Val558Ile Uncertain significance ★★ ⚠ same residue
INPP5E p.Val558Leu Uncertain significance ★ ⚠ same residue
INPP5E c.937-2A>G 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.Tyr543Ter Pathogenic ★★ same condition
INPP5E p.Val303Met 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-val558phe (accessed [today's date]).

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