Is IPO7 p.Phe462Leu (c.1386C>G) pathogenic?

IPO7 p.Phe462Leu (c.1386C>G) is classified Uncertain significance in IPO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely pathogenic (0.9913); Very rare (popmax 0.00518%, amr).

How common is IPO7 p.Phe462Leu (c.1386C>G) in the general population?

IPO7 p.Phe462Leu (c.1386C>G) is very rare (popmax 0.00518%, amr) (gnomAD).

What do computational predictors say about IPO7 p.Phe462Leu (c.1386C>G)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

IPO7 p.Phe462Leu

c.1386C>G · rs1288731763 · VCV3110336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00518%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic
REVEL	0.385	indeterminate
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.65	GERP -4.2, phastCons 0.014
Regional constraint	o/e 0.57	unconstrained · MANE · 6,071 bp · p 1.6e-10 · regional, not allelic
Overall
CADD	20.9	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 0.00518% Admixed American · 3/57,862 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000681%

Overall 0.00019% 3/1,581,100 alleles · very rare exomes 2/1,429,036 · genomes 1/152,064 · 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: IPO7
Protein: p.Phe462Leu
Coding: c.1386C>G
MANE Select: NM_006391
dbSNP: rs1288731763
Type: single nucleotide variant
Location: chr11:9428590 (GRCh38)
Gene constraint: LOEUF 0.138 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.24

Full IPO7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IPO7 p.Ala363Gly Uncertain significance ★ ⚠ same type
IPO7 p.Ala74Ser Uncertain significance ★ ⚠ same type
IPO7 p.Ala764Gly Uncertain significance ★ ⚠ same type
IPO7 p.Ala786Gly Uncertain significance ★ ⚠ same type
IPO7 p.Ala843Ser Uncertain significance ★ ⚠ same type
IPO7 p.Ala923Gly Uncertain significance ★ ⚠ same type
IPO7 p.Ala979Thr Uncertain significance ★ ⚠ same type
IPO7 p.Arg125His 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/ipo7-p-phe462leu (accessed [today's date]).

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