Is IPO9 p.Lys348Ile (c.1043A>T) pathogenic?

IPO9 p.Lys348Ile (c.1043A>T) is classified Uncertain significance in IPO9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-29). AlphaMissense: likely pathogenic (0.847); Very rare (popmax 0.00203%, nfe).

How common is IPO9 p.Lys348Ile (c.1043A>T) in the general population?

IPO9 p.Lys348Ile (c.1043A>T) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about IPO9 p.Lys348Ile (c.1043A>T)?

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

IPO9 p.Lys348Ile

c.1043A>T · rs765881694 · VCV2597412

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.847	likely pathogenic
REVEL	0.56	indeterminate
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 42 kb · p 3e-18 · regional, not allelic
Overall
CADD	27.3	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 0.00203% European (non-Finnish) · 24/1,179,620 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00155% 25/1,612,398 alleles · very rare exomes 23/1,460,184 · genomes 2/152,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,151
Remaining individualsnot grpmax-eligible	0.0016%	62,408

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.Lys348Ile
Coding: c.1043A>T
MANE Select: NM_018085
dbSNP: rs765881694
Type: single nucleotide variant
Location: chr1:201855855 (GRCh38)
Gene constraint: LOEUF 0.31 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 7 PDB
Residue 348: a turn

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-lys348ile (accessed [today's date]).

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