Is IPO8 p.Arg181Cys (c.541C>T) pathogenic?

IPO8 p.Arg181Cys (c.541C>T) is classified Uncertain significance in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: likely benign (0.1614); Very rare (popmax 0.00401%, afr).

How common is IPO8 p.Arg181Cys (c.541C>T) in the general population?

IPO8 p.Arg181Cys (c.541C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about IPO8 p.Arg181Cys (c.541C>T)?

AlphaMissense predicts likely benign (score 0.1614) — an in-silico prediction, not a clinical call.

IPO8 p.Arg181Cys

c.541C>T · VCV3341935

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1614	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.1	GERP 0.31, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	25.7	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 0.00401% African / African-American · 3/74,856 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00118% 19/1,612,178 alleles · very rare exomes 15/1,460,078 · genomes 4/152,100 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,952
Remaining individualsnot grpmax-eligible	0.0032%	31,202
European (non-Finnish)	0.00119%	84,202

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.Arg181Cys
Coding: c.541C>T
MANE Select: NM_006390
Type: single nucleotide variant
Location: chr12:30680580 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 181: 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

Similar variants

IPO8 c.2900-1G>A Pathogenic/Likely pathogenic ★★ same type
IPO8 p.Arg474Ter Pathogenic ★★ same type
IPO8 p.Arg803Ter Pathogenic/Likely pathogenic ★★ same type
IPO8 p.Trp259Ter Pathogenic ★★ same type
IPO8 p.Ala877Asp Uncertain significance ★★ ⚠ same type
IPO8 p.Ala941Val Uncertain significance ★★ ⚠ same type
IPO8 p.Arg1002Trp Uncertain significance ★★ ⚠ same type
IPO8 p.Arg884Gln Uncertain significance ★★ ⚠ same type

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-arg181cys (accessed [today's date]).

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