Is IPO8 p.Gln28Ter (c.82C>T) pathogenic?

IPO8 p.Gln28Ter (c.82C>T) is classified Pathogenic in IPO8 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-03-09). Very rare (popmax 8.48e-05%, nfe); Associated with VISS syndrome.

What condition is associated with IPO8 p.Gln28Ter (c.82C>T)?

IPO8 p.Gln28Ter (c.82C>T) is associated with VISS syndrome (ClinVar).

How common is IPO8 p.Gln28Ter (c.82C>T) in the general population?

IPO8 p.Gln28Ter (c.82C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

IPO8 p.Gln28Ter

c.82C>T · rs2053331144 · VCV1064722

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

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

Conditions

VISS syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 25
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -0.85, phastCons 1
Overall
CADD	44.0	PHRED · no single calibrated threshold — expert panels disagree

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) · 1/1,179,828 alleles

Overall 6.2e-05% 1/1,613,886 alleles · very rare exomes 1/1,461,596 · genomes 0/152,290 · 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.Gln28Ter
Coding: c.82C>T
MANE Select: NM_006390
dbSNP: rs2053331144
Type: single nucleotide variant
Location: chr12:30695566 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 28: the importin n-terminal domain; 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)

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.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
IPO8 p.Arg234Ter Likely 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-gln28ter (accessed [today's date]).

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