Is IPO8 p.Arg834Trp (c.2500C>T) pathogenic?

IPO8 p.Arg834Trp (c.2500C>T) is classified Likely pathogenic in IPO8 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-03-09). AlphaMissense: likely pathogenic (0.953); Very rare (popmax 0.00223%, eas); Associated with VISS syndrome.

What condition is associated with IPO8 p.Arg834Trp (c.2500C>T)?

IPO8 p.Arg834Trp (c.2500C>T) is associated with VISS syndrome (ClinVar).

How common is IPO8 p.Arg834Trp (c.2500C>T) in the general population?

IPO8 p.Arg834Trp (c.2500C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about IPO8 p.Arg834Trp (c.2500C>T)?

AlphaMissense predicts likely pathogenic (score 0.953) — an in-silico prediction, not a clinical call.

IPO8 p.Arg834Trp

c.2500C>T · rs1425433912 · VCV1064726

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

VISS syndrome

Computational evidence

Protein change
AlphaMissense	0.953	likely pathogenic ✓ concordant with ClinVar
REVEL	0.737	pathogenic-leaning
SaProt	LLR -13.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.00223% East Asian · 1/44,858 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,612,064 alleles · very rare exomes 6/1,460,056 · genomes 0/152,008 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,858
European (non-Finnish)	0.000424%	235,851

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.Arg834Trp
Coding: c.2500C>T
MANE Select: NM_006390
dbSNP: rs1425433912
Type: single nucleotide variant
Location: chr12:30637177 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 834: 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); a UniProt-annotated variant site (in viss; very low protein expression levels, if any, 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-arg834trp (accessed [today's date]).

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