Is IPO8 p.Phe82Ser (c.245T>C) pathogenic?

IPO8 p.Phe82Ser (c.245T>C) is classified Uncertain significance in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.9847); Absent from gnomAD v4.1; Associated with Thoracic aortic aneurysm or dissection.

What condition is associated with IPO8 p.Phe82Ser (c.245T>C)?

IPO8 p.Phe82Ser (c.245T>C) is associated with Thoracic aortic aneurysm or dissection (ClinVar).

How common is IPO8 p.Phe82Ser (c.245T>C) in the general population?

IPO8 p.Phe82Ser (c.245T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IPO8 p.Phe82Ser (c.245T>C)?

AlphaMissense predicts likely pathogenic (score 0.9847) — an in-silico prediction, not a clinical call.

IPO8 p.Phe82Ser

c.245T>C · VCV4533348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9847 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Thoracic aortic aneurysm or dissection

Computational evidence

Protein change
AlphaMissense	0.9847	likely pathogenic · top 6% in IPO8
REVEL	0.435	indeterminate
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP -1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	24.5	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

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.Phe82Ser
Coding: c.245T>C
MANE Select: NM_006390
Type: single nucleotide variant
Location: chr12:30684379 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 82: 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

Thoracic aortic aneurysm or dissection

Similar variants

IPO8 c.2900-1G>A Pathogenic/Likely pathogenic ★★ same condition
IPO8 p.Arg474Ter Pathogenic ★★ same condition
IPO8 p.Trp259Ter Pathogenic ★★ same condition
IPO8 c.1428+5G>A Pathogenic ★ same condition
IPO8 p.Arg971Ter Likely pathogenic ★ same condition
IPO8 p.Trp229Ter Pathogenic ★ same condition
IPO8 p.Glu688Asp Uncertain significance ★ ⚠ same condition
IPO8 p.Ser657Tyr 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-phe82ser (accessed [today's date]).

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