Is IPO8 p.Leu294Phe (c.882G>C) pathogenic?

IPO8 p.Leu294Phe (c.882G>C) is classified Uncertain significance in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.7296); Very rare (popmax 0.00499%, nfe); Associated with Inborn genetic diseases.

What condition is associated with IPO8 p.Leu294Phe (c.882G>C)?

IPO8 p.Leu294Phe (c.882G>C) is associated with Inborn genetic diseases (ClinVar).

How common is IPO8 p.Leu294Phe (c.882G>C) in the general population?

IPO8 p.Leu294Phe (c.882G>C) is very rare (popmax 0.00499%, nfe) (gnomAD).

What do computational predictors say about IPO8 p.Leu294Phe (c.882G>C)?

AlphaMissense predicts likely pathogenic (score 0.7296) — an in-silico prediction, not a clinical call.

IPO8 p.Leu294Phe

c.882G>C · VCV4276198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00499%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7296	likely pathogenic
REVEL	0.407	indeterminate
SaProt	LLR -7.95	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	24.3	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 0.00499% European (non-Finnish) · 58/1,163,058 alleles

Filtering AF 0.00391% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00358%

Overall 0.00365% 58/1,590,574 alleles · very rare exomes 58/1,438,330 · genomes 0/152,244 · joint denominator

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.Leu294Phe
Coding: c.882G>C
MANE Select: NM_006390
Type: single nucleotide variant
Location: chr12:30674017 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 294: 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)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IPO8 p.Ala877Asp Uncertain significance ★★ ⚠ same condition
IPO8 p.Ala941Val Uncertain significance ★★ ⚠ same condition
IPO8 p.Arg1002Trp Uncertain significance ★★ ⚠ same condition
IPO8 p.Arg884Gln Uncertain significance ★★ ⚠ same condition
IPO8 p.Asn953Asp Uncertain significance ★★ ⚠ same condition
IPO8 p.His435Arg Uncertain significance ★★ ⚠ same condition
IPO8 p.Lys533Asn Uncertain significance ★★ ⚠ same condition
IPO8 p.Pro423Leu Uncertain significance ★★ ⚠ same condition

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-leu294phe (accessed [today's date]).

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