Is IPO4 p.Leu123Phe (c.367C>T) pathogenic?

IPO4 p.Leu123Phe (c.367C>T) is classified Uncertain significance in IPO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: ambiguous (0.4383); Absent from gnomAD v4.1.

How common is IPO4 p.Leu123Phe (c.367C>T) in the general population?

IPO4 p.Leu123Phe (c.367C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IPO4 p.Leu123Phe (c.367C>T)?

AlphaMissense predicts ambiguous (score 0.4383) — an in-silico prediction, not a clinical call.

IPO4 p.Leu123Phe

c.367C>T · VCV4039178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4383 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4383	ambiguous
REVEL	0.113	moderately benign-leaning
SaProt	LLR -10.51	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,391 bp · p 0.73 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IPO4
Protein: p.Leu123Phe
Coding: c.367C>T
MANE Select: NM_024658
Type: single nucleotide variant
Location: chr14:24187708 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 4 PDB
Residue 123: an α-helix

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

Similar variants

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
IMP4 p.Arg198Gln 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-leu123phe (accessed [today's date]).

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