Is IPO8 p.Arg474Ter (c.1420C>T) pathogenic?

IPO8 p.Arg474Ter (c.1420C>T) is classified Pathogenic in IPO8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-29). Very rare (popmax 0.00137%, afr); Associated with IPO8-related aortopathy.

What condition is associated with IPO8 p.Arg474Ter (c.1420C>T)?

IPO8 p.Arg474Ter (c.1420C>T) is associated with IPO8-related aortopathy (ClinVar).

How common is IPO8 p.Arg474Ter (c.1420C>T) in the general population?

IPO8 p.Arg474Ter (c.1420C>T) is very rare (popmax 0.00137%, afr) (gnomAD).

IPO8 p.Arg474Ter

c.1420C>T · rs1160566841 · VCV1047908

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Conditions

IPO8-related aortopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 25
Splicing
SpliceAI	Δ0.38	donor loss, 8 bp away · masked 0 · deltas
Pangolin	Δ0.58	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.5	GERP 1.8, phastCons 1
Overall
CADD	47.0	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 0.00137% African / African-American · 1/73,002 alleles

Filtering AF 8.4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.6e-05%

Overall 0.000325% 5/1,540,734 alleles · very rare exomes 5/1,388,482 · genomes 0/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00137%	73,002
European (non-Finnish)	0.000357%	280,150

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.Arg474Ter
Coding: c.1420C>T
MANE Select: NM_006390
dbSNP: rs1160566841
Type: single nucleotide variant
Location: chr12:30665228 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 474: 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

IPO8-related aortopathy

Similar variants

IPO8 c.2900-1G>A Pathogenic/Likely 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.Phe82Ser 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-arg474ter (accessed [today's date]).

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