Is IPO9 p.Pro912Ala (c.2734C>G) pathogenic?

IPO9 p.Pro912Ala (c.2734C>G) is classified Uncertain significance in IPO9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.5306); Very rare (popmax 8.48e-05%, nfe).

How common is IPO9 p.Pro912Ala (c.2734C>G) in the general population?

IPO9 p.Pro912Ala (c.2734C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about IPO9 p.Pro912Ala (c.2734C>G)?

AlphaMissense predicts ambiguous (score 0.5306) — an in-silico prediction, not a clinical call.

IPO9 p.Pro912Ala

c.2734C>G · VCV4039213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5306 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5306	ambiguous
REVEL	0.616	indeterminate
SaProt	LLR -11.80	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 4,766 bp · p 0.00019 · regional, not allelic
Overall
CADD	25.3	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 8.48e-05% European (non-Finnish) · 1/1,179,858 alleles

Overall 6.2e-05% 1/1,613,908 alleles · very rare exomes 1/1,461,646 · genomes 0/152,262 · 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.Pro912Ala
Coding: c.2734C>G
MANE Select: NM_018085
Type: single nucleotide variant
Location: chr1:201874273 (GRCh38)
Gene constraint: LOEUF 0.31 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 7 PDB
Residue 912: a β-strand

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-pro912ala (accessed [today's date]).

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