Is IPO4 p.Arg899Gln (c.2696G>A) pathogenic?

IPO4 p.Arg899Gln (c.2696G>A) is classified Uncertain significance in IPO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.0941); Ultra-rare (popmax 0.0538%, sas).

How common is IPO4 p.Arg899Gln (c.2696G>A) in the general population?

IPO4 p.Arg899Gln (c.2696G>A) is ultra-rare (popmax 0.0538%, sas) (gnomAD).

What do computational predictors say about IPO4 p.Arg899Gln (c.2696G>A)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

IPO4 p.Arg899Gln

c.2696G>A · VCV4039170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0538%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -3.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP -0.57, phastCons 0.94
Regional constraint	o/e 0.88	unconstrained · MANE · 3,885 bp · p 0.0022 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0538% South Asian · 49/91,092 alleles

Filtering AF 0.0417% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0374%

Overall 0.0113% 183/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.26%	385
South Asiangrpmax	0.0538%	1,859
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0304%	3,290
Admixed American	0.00833%	12,005
European (non-Finnish)	0.00263%	38,065

Ashkenazi Jewish 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: IPO4
Protein: p.Arg899Gln
Coding: c.2696G>A
MANE Select: NM_024658
Type: single nucleotide variant
Location: chr14:24182066 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 4 PDB
Residue 899: an α-helix

Full IPO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IPO4 p.Arg899Trp Uncertain significance ★ ⚠ same residue
IPO4 p.Arg20Cys Benign ★★ ⚠ same type
IPO4 p.Pro494Thr Benign ★★ same type
IMP4 p.Ala21Val Uncertain significance ★ ⚠ same type
IMP4 p.Ala282Thr Uncertain significance ★ ⚠ same type
IMP4 p.Arg126Gln Uncertain significance ★ ⚠ same type
IMP4 p.Arg170Trp Uncertain significance ★ ⚠ same type
IMP4 p.Arg194Cys 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/ipo4-p-arg899gln (accessed [today's date]).

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