Is IPO4 p.Ser47Leu (c.140C>T) pathogenic?

IPO4 p.Ser47Leu (c.140C>T) is classified Uncertain significance in IPO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.0988); Very rare (popmax 0.000763%, nfe).

How common is IPO4 p.Ser47Leu (c.140C>T) in the general population?

IPO4 p.Ser47Leu (c.140C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about IPO4 p.Ser47Leu (c.140C>T)?

AlphaMissense predicts likely benign (score 0.0988) — an in-silico prediction, not a clinical call.

IPO4 p.Ser47Leu

c.140C>T · rs751437225 · VCV3110322

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0988	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -8.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 0.59, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,391 bp · p 0.73 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,650 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,612,832 alleles · very rare exomes 7/1,460,592 · genomes 2/152,240 · joint denominator

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: IPO4
Protein: p.Ser47Leu
Coding: c.140C>T
MANE Select: NM_024658
dbSNP: rs751437225
Type: single nucleotide variant
Location: chr14:24188568 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 4 PDB
Residue 47: the importin n-terminal domain

Full IPO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IMP4 p.Arg47His Uncertain significance ★ ⚠ same residue
IPO4 p.Arg20Cys Benign ★★ ⚠ same type
IPO4 p.Pro494Thr Benign ★★ same type
IMP4 p.Ala21Val Uncertain significance ★ ⚠ same type
IMP4 p.Ala282Thr Uncertain significance ★ ⚠ same type
IMP4 p.Arg126Gln Uncertain significance ★ ⚠ same type
IMP4 p.Arg170Trp Uncertain significance ★ ⚠ same type
IMP4 p.Arg194Cys 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/ipo4-p-ser47leu (accessed [today's date]).

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