IPO8 p.Leu323=
c.969T>C · VCV4853431
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Common
common (popmax 67.4%, afr) — too common for a highly-penetrant pathogenic allele
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 1 | GERP -4, phastCons 0.99 |
| Overall | ||
| CADD | 5.349 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
67.4%
African / African-American · 50,407/74,816 alleles
Filtering AF
66.9%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 66.7%
Overall
51.4%
827,227/1,609,624 alleles · common
exomes 744,116/1,457,646 · genomes 83,111/151,978 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 67.4% | 1 |
| Finnishnot grpmax-eligible | 59% | 2 |
| Ashkenazi Jewishnot grpmax-eligible | 55.1% | 2 |
| Middle Eastern | 54.6% | 2 |
| European (non-Finnish) | 51.8% | 2 |
| Remaining individualsnot grpmax-eligible | 51.2% | 2 |
| East Asian | 46.1% | 2 |
| South Asian | 42.2% | 2 |
| Amishnot grpmax-eligible | 33.7% | 3 |
| Admixed American | 30.9% | 3 |
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.Leu323=
- Coding
- c.969T>C
- MANE Select
- NM_006390
- Type
- single nucleotide variant
- Location
- chr12:30671037 (GRCh38)
- Gene constraint
- LOEUF 0.575 · pLI 0.15 (gnomAD)
- Structure
- AlphaFold pLDDT 87.59
- Residue 323
- 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)
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-leu323 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown