Is IPO8 p.Leu741Arg (c.2222T>G) pathogenic?

IPO8 p.Leu741Arg (c.2222T>G) is classified Uncertain significance in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-26). AlphaMissense: likely pathogenic (0.9913); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with IPO8 p.Leu741Arg (c.2222T>G)?

IPO8 p.Leu741Arg (c.2222T>G) is associated with Inborn genetic diseases (ClinVar).

How common is IPO8 p.Leu741Arg (c.2222T>G) in the general population?

IPO8 p.Leu741Arg (c.2222T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IPO8 p.Leu741Arg (c.2222T>G)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

IPO8 p.Leu741Arg

c.2222T>G · rs2497989874 · VCV2291332

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic · top 3% in IPO8
REVEL	0.828	moderately pathogenic-leaning
SaProt	LLR -16.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IPO8
Protein: p.Leu741Arg
Coding: c.2222T>G
MANE Select: NM_006390
dbSNP: rs2497989874
Type: single nucleotide variant
Location: chr12:30649183 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 741: 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

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-leu741arg (accessed [today's date]).

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