Is IPO8 p.Lys591Arg (c.1772A>G) pathogenic?

IPO8 p.Lys591Arg (c.1772A>G) is classified Likely benign in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-04). AlphaMissense: likely benign (0.0754); Rare (popmax 0.347%, afr).

How common is IPO8 p.Lys591Arg (c.1772A>G) in the general population?

IPO8 p.Lys591Arg (c.1772A>G) is rare (popmax 0.347%, afr) (gnomAD).

What do computational predictors say about IPO8 p.Lys591Arg (c.1772A>G)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

IPO8 p.Lys591Arg

c.1772A>G · VCV4887513

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.347%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.78, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	18.35	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 0.347% African / African-American · 256/73,718 alleles

Filtering AF 0.312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.299%

Overall 0.0168% 268/1,593,432 alleles · rare exomes 129/1,441,122 · genomes 139/152,310 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.347%	288
Remaining individualsnot grpmax-eligible	0.013%	7,705
Admixed American	0.00533%	18,773
European (non-Finnish)	8.53e-05%	1,171,690

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: IPO8
Protein: p.Lys591Arg
Coding: c.1772A>G
MANE Select: NM_006390
Type: single nucleotide variant
Location: chr12:30661250 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 591: a UniProt-annotated variant site (in viss; undetectable protein levels in either patient's fibroblasts or patient's epstein-barr virus-immortalized b cell lines); a UniProt-annotated variant site (in viss); a UniProt-annotated variant site (in viss; undetectable protein levels in patient's fibroblasts, although mrna levels seem unaffected)

Full IPO8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IPO8 c.2900-1G>A Pathogenic/Likely pathogenic ★★ same type
IPO8 p.Arg474Ter Pathogenic ★★ same type
IPO8 p.Arg803Ter Pathogenic/Likely pathogenic ★★ same type
IPO8 p.Trp259Ter Pathogenic ★★ same type
IPO8 p.Ala877Asp Uncertain significance ★★ ⚠ same type
IPO8 p.Ala941Val Uncertain significance ★★ ⚠ same type
IPO8 p.Arg1002Trp Uncertain significance ★★ ⚠ same type
IPO8 p.Arg884Gln 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/ipo8-p-lys591arg (accessed [today's date]).

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