Is IPO8 p.Val257fs (c.770_777del) pathogenic?

IPO8 p.Val257fs (c.770777del) is classified Pathogenic in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-18). Very rare (popmax 8.48e-05%, nfe); Associated with IPO8-related aortopathy.

What condition is associated with IPO8 p.Val257fs (c.770_777del)?

IPO8 p.Val257fs (c.770_777del) is associated with IPO8-related aortopathy (ClinVar).

How common is IPO8 p.Val257fs (c.770_777del) in the general population?

IPO8 p.Val257fs (c.770_777del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

IPO8 p.Val257fs

c.770_777del · rs2136163711 · VCV1047909

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

IPO8-related aortopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,756 alleles

Overall 6.2e-05% 1/1,613,692 alleles · very rare exomes 1/1,461,568 · genomes 0/152,124 · 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.Val257fs
Coding: c.770_777del
MANE Select: NM_006390
dbSNP: rs2136163711
Type: Deletion
Location: chr12:30674706 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 257: 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

IPO8-related aortopathy

Similar variants

IPO8 p.Leu783fs Pathogenic ★ same condition
IPO8 p.Leu866fs Pathogenic ★ same condition
IPO8 c.2695+3_2695+7del Pathogenic same condition
IPO8 p.Pro243fs Pathogenic same condition
IPO8 p.Pro513fs Pathogenic same condition
IPO8 c.2900-1G>A Pathogenic/Likely pathogenic ★★ same condition
IPO8 p.Arg474Ter Pathogenic ★★ same condition
IPO8 p.Trp259Ter Pathogenic ★★ 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-val257fs (accessed [today's date]).

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