Is IPO8 p.Arg1002Trp (c.3004C>T) pathogenic?

IPO8 p.Arg1002Trp (c.3004C>T) is classified Uncertain significance in IPO8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-13). AlphaMissense: likely benign (0.1765); Ultra-rare (popmax 0.0481%, afr); Associated with Inborn genetic diseases.

What condition is associated with IPO8 p.Arg1002Trp (c.3004C>T)?

IPO8 p.Arg1002Trp (c.3004C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IPO8 p.Arg1002Trp (c.3004C>T) in the general population?

IPO8 p.Arg1002Trp (c.3004C>T) is ultra-rare (popmax 0.0481%, afr) (gnomAD).

What do computational predictors say about IPO8 p.Arg1002Trp (c.3004C>T)?

AlphaMissense predicts likely benign (score 0.1765) — an in-silico prediction, not a clinical call.

IPO8 p.Arg1002Trp

c.3004C>T · rs151232989 · VCV2406850

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1765 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0481%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1765	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -13.06	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	phastCons 0.94
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	25.0	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 0.0481% African / African-American · 36/74,826 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00391% 63/1,610,626 alleles · ultra-rare exomes 36/1,458,466 · genomes 27/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0481%	2,079
Remaining individualsnot grpmax-eligible	0.00963%	10,388
East Asian	0.00891%	11,218
Admixed American	0.00834%	11,989
South Asian	0.0044%	22,734
European (non-Finnish)	0.000679%	147,331

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.Arg1002Trp
Coding: c.3004C>T
MANE Select: NM_006390
dbSNP: rs151232989
Type: single nucleotide variant
Location: chr12:30631907 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 1002: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IPO8 p.Arg1002Gln Uncertain significance ★ ⚠ same residue
IPO8 p.Arg1002= Likely benign ★ same residue
IPO8 p.Ala877Asp Uncertain significance ★★ ⚠ same condition
IPO8 p.Ala941Val Uncertain significance ★★ ⚠ same condition
IPO8 p.Arg884Gln Uncertain significance ★★ ⚠ same condition
IPO8 p.Asn953Asp Uncertain significance ★★ ⚠ same condition
IPO8 p.His435Arg Uncertain significance ★★ ⚠ same condition
IPO8 p.Lys533Asn 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-arg1002trp (accessed [today's date]).

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