Is IPO8 p.Lys406fs (c.1216_1220del) pathogenic?

IPO8 p.Lys406fs (c.12161220del) is classified Likely pathogenic in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-15). Very rare (popmax 0.000867%, nfe); Associated with VISS syndrome.

What condition is associated with IPO8 p.Lys406fs (c.1216_1220del)?

IPO8 p.Lys406fs (c.1216_1220del) is associated with VISS syndrome (ClinVar).

How common is IPO8 p.Lys406fs (c.1216_1220del) in the general population?

IPO8 p.Lys406fs (c.1216_1220del) is very rare (popmax 0.000867%, nfe) (gnomAD).

IPO8 p.Lys406fs

c.1216_1220del · VCV3387778

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000867%, nfe)

Conditions

VISS syndrome

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 11 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	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 0.000867% European (non-Finnish) · 10/1,153,190 alleles

Filtering AF 0.000439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00032%

Overall 0.000769% 12/1,561,328 alleles · very rare exomes 12/1,409,138 · genomes 0/152,190 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00166%	60,386
Finnishnot grpmax-eligible	0.0016%	62,540
European (non-Finnish)grpmax	0.000867%	115,319

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys406fs
Coding: c.1216_1220del
MANE Select: NM_006390
Type: Microsatellite
Location: chr12:30666176 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 406: 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

VISS syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IPO8 c.2900-1G>A Pathogenic/Likely pathogenic ★★ same condition
IPO8 p.Arg803Ter Pathogenic/Likely pathogenic ★★ same condition
IPO8 p.Ser357fs Pathogenic/Likely pathogenic ★★ same condition
IPO8 p.Trp259Ter Pathogenic ★★ same condition
IPO8 p.Leu709Pro Uncertain significance ★★ ⚠ same condition
IPO8 c.1428+5G>A Pathogenic ★ same condition
IPO8 c.1756-1G>T Likely pathogenic ★ same condition
IPO8 c.639+1G>A 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-lys406fs (accessed [today's date]).

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