Is IPO11 p.Arg76His (c.227G>A) pathogenic?

IPO11 p.Arg76His (c.227G>A) is classified Uncertain significance in IPO11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely benign (0.2437); Very rare (popmax 0.00269%, afr).

How common is IPO11 p.Arg76His (c.227G>A) in the general population?

IPO11 p.Arg76His (c.227G>A) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about IPO11 p.Arg76His (c.227G>A)?

AlphaMissense predicts likely benign (score 0.2437) — an in-silico prediction, not a clinical call.

IPO11 p.Arg76His

c.227G>A · VCV4679220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2437 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2437	likely benign
REVEL	0.414	indeterminate
SaProt	LLR -11.22	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 48 kb · p 0.2 · regional, not allelic
Overall
CADD	29.7	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 0.00269% African / African-American · 2/74,432 alleles

Filtering AF 0.000961% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000793%

Overall 0.00131% 21/1,600,982 alleles · very rare exomes 20/1,448,858 · genomes 1/152,124 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,216
Remaining individualsnot grpmax-eligible	0.00161%	62,012
European (non-Finnish)	0.00154%	65,033

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: IPO11
Protein: p.Arg76His
Coding: c.227G>A
MANE Select: NM_016338
Type: single nucleotide variant
Location: chr5:62443071 (GRCh38)
Gene constraint: LOEUF 0.598 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 93.53
Residue 76: the importin n-terminal domain

Full IPO11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IPO11 p.Thr409Ala Uncertain significance ★★ ⚠ same type
IPO11 p.Ala726= Benign ★★ same type
IPO11 p.Asn260Asp Benign ★★ same type
IPO11 p.Leu112= Benign ★★ same type
IPO11 p.Leu246= Benign ★★ same type
IPO11 p.Leu799= Benign ★★ same type
IPO11 p.Ala110Val Uncertain significance ★ ⚠ same type
IPO11 p.Ala332Thr 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/ipo11-p-arg76his (accessed [today's date]).

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