Is IPO9 p.Val522Ala (c.1565T>C) pathogenic?

IPO9 p.Val522Ala (c.1565T>C) is classified Uncertain significance in IPO9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). AlphaMissense: ambiguous (0.4701); Very rare (popmax 0.00167%, amr).

How common is IPO9 p.Val522Ala (c.1565T>C) in the general population?

IPO9 p.Val522Ala (c.1565T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about IPO9 p.Val522Ala (c.1565T>C)?

AlphaMissense predicts ambiguous (score 0.4701) — an in-silico prediction, not a clinical call.

IPO9 p.Val522Ala

c.1565T>C · VCV4679272

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.4701	ambiguous
REVEL	0.601	indeterminate
SaProt	LLR -10.05	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 42 kb · p 3e-18 · regional, not allelic
Overall
CADD	27.1	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 0.00167% Admixed American · 1/59,934 alleles

Overall 6.22e-05% 1/1,607,084 alleles · very rare exomes 0/1,454,924 · genomes 1/152,160 · 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: IPO9
Protein: p.Val522Ala
Coding: c.1565T>C
MANE Select: NM_018085
Type: single nucleotide variant
Location: chr1:201863544 (GRCh38)
Gene constraint: LOEUF 0.31 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 7 PDB
Residue 522: an α-helix

Full IPO9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IPO9 p.Gln558= Benign ★★ same type
IPO9 p.Ala10Val Uncertain significance ★ ⚠ same type
IPO9 p.Ala131Val Uncertain significance ★ ⚠ same type
IPO9 p.Ala166Pro Uncertain significance ★ ⚠ same type
IPO9 p.Ala342Gly Uncertain significance ★ ⚠ same type
IPO9 p.Ala418Gly Uncertain significance ★ ⚠ same type
IPO9 p.Ala425Thr Uncertain significance ★ ⚠ same type
IPO9 p.Ala498Ser Uncertain significance ★ ⚠ same type

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/ipo9-p-val522ala (accessed [today's date]).

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