Is IPO8 p.Phe292Ile (c.874T>A) pathogenic?

IPO8 p.Phe292Ile (c.874T>A) is classified Uncertain significance in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-13). AlphaMissense: ambiguous (0.4472); Very rare (popmax 8.59e-05%, nfe).

How common is IPO8 p.Phe292Ile (c.874T>A) in the general population?

IPO8 p.Phe292Ile (c.874T>A) is very rare (popmax 8.59e-05%, nfe) (gnomAD).

What do computational predictors say about IPO8 p.Phe292Ile (c.874T>A)?

AlphaMissense predicts ambiguous (score 0.4472) — an in-silico prediction, not a clinical call.

IPO8 p.Phe292Ile

c.874T>A · rs2498086490 · VCV2499284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.59e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4472	ambiguous
REVEL	0.141	moderately benign-leaning
SaProt	LLR -6.53	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.72, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	24.0	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 8.59e-05% European (non-Finnish) · 1/1,164,288 alleles

Overall 6.28e-05% 1/1,592,342 alleles · very rare exomes 1/1,439,976 · genomes 0/152,366 · 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: IPO8
Protein: p.Phe292Ile
Coding: c.874T>A
MANE Select: NM_006390
dbSNP: rs2498086490
Type: single nucleotide variant
Location: chr12:30674025 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 292: 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); a UniProt-annotated variant site (in viss)

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-phe292ile (accessed [today's date]).

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