Is IPO8 p.Leu709Pro (c.2126T>C) pathogenic?

IPO8 p.Leu709Pro (c.2126T>C) is classified Uncertain significance in IPO8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-23). AlphaMissense: likely pathogenic (0.9512); Absent from gnomAD v4.1; Associated with VISS syndrome.

What condition is associated with IPO8 p.Leu709Pro (c.2126T>C)?

IPO8 p.Leu709Pro (c.2126T>C) is associated with VISS syndrome (ClinVar).

How common is IPO8 p.Leu709Pro (c.2126T>C) in the general population?

IPO8 p.Leu709Pro (c.2126T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IPO8 p.Leu709Pro (c.2126T>C)?

AlphaMissense predicts likely pathogenic (score 0.9512) — an in-silico prediction, not a clinical call.

IPO8 p.Leu709Pro

c.2126T>C · rs2052737583 · VCV2664318

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9512 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

VISS syndrome

Computational evidence

Protein change
AlphaMissense	0.9512	likely pathogenic
REVEL	0.646	pathogenic-leaning
SaProt	LLR -15.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	26.8	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.Leu709Pro
Coding: c.2126T>C
MANE Select: NM_006390
dbSNP: rs2052737583
Type: single nucleotide variant
Location: chr12:30652238 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 709: 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

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 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
IPO8 p.Arg834Trp 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-leu709pro (accessed [today's date]).

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