Is IPO4 p.Arg584His (c.1751G>A) pathogenic?

IPO4 p.Arg584His (c.1751G>A) is classified Uncertain significance in IPO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-30). AlphaMissense: ambiguous (0.3625); Very rare (popmax 0.00695%, eas).

How common is IPO4 p.Arg584His (c.1751G>A) in the general population?

IPO4 p.Arg584His (c.1751G>A) is very rare (popmax 0.00695%, eas) (gnomAD).

What do computational predictors say about IPO4 p.Arg584His (c.1751G>A)?

AlphaMissense predicts ambiguous (score 0.3625) — an in-silico prediction, not a clinical call.

IPO4 p.Arg584His

c.1751G>A · VCV3286316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3625 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3625	ambiguous
REVEL	0.284	benign-leaning
SaProt	LLR -9.71	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 3,885 bp · p 0.0022 · regional, not allelic
Overall
CADD	31.0	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 0.00695% East Asian · 3/43,154 alleles

Filtering AF 0.00184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000911%

Overall 0.000506% 8/1,581,916 alleles · very rare exomes 7/1,429,790 · genomes 1/152,126 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00695%	14,385
European (non-Finnish)	0.000429%	232,842

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.Arg584His
Coding: c.1751G>A
MANE Select: NM_024658
Type: single nucleotide variant
Location: chr14:24184304 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 4 PDB
Residue 584: a turn

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

Similar variants

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
IMP4 p.Arg198Gln 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-arg584his (accessed [today's date]).

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