Is IRF2BPL p.Pro290fs (c.869del) pathogenic?

IRF2BPL p.Pro290fs (c.869del) is classified Likely pathogenic in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-23). Very rare (popmax 7.54e-05%); Associated with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures.

How common is IRF2BPL p.Pro290fs (c.869del) in the general population?

IRF2BPL p.Pro290fs (c.869del) is very rare (popmax 7.54e-05%) (gnomAD).

IRF2BPL p.Pro290fs

Q: What condition is associated with IRF2BPL p.Pro290fs (c.869del)?

IRF2BPL p.Pro290fs (c.869del) is associated with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (ClinVar).

Q: How is IRF2BPL-related regressive neurodevelopmental disorder-dystonia-seizures syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.869del · VCV4849977

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 7.54e-05%)

Conditions

neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -9.9	GERP -2.5

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.54e-05%

Overall 7.54e-05% 1/1,326,264 alleles · very rare

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: IRF2BPL
Protein: p.Pro290fs
Coding: c.869del
MANE Select: NM_024496
Type: Deletion
Location: chr14:77026924 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 290: the 'disordered' region; a UniProt-annotated variant site (in nedamss); a UniProt-annotated variant site (in nedamss; loss of function)

Full IRF2BPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For IRF2BPL-related regressive neurodevelopmental disorder-dystonia-seizures syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy, Neonatal

Similar variants

IRF2BPL p.Ala101fs Likely pathogenic ★★ same condition
IRF2BPL p.Asn701fs Pathogenic ★★ same condition
IRF2BPL p.Gln113fs Benign/Likely benign ★★ same condition
IRF2BPL p.Gln127del Benign ★★ same condition
IRF2BPL p.Ala138fs Pathogenic ★ same condition
IRF2BPL p.Ala159fs Pathogenic ★ same condition
IRF2BPL p.Ala162fs Likely pathogenic ★ same condition
IRF2BPL p.Ala94fs Pathogenic ★ same condition

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/irf2bpl-p-pro290fs (accessed [today's date]).

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