Is IRF2BPL p.Phe64fs (c.188_191dup) pathogenic?

IRF2BPL p.Phe64fs (c.188191dup) is classified Pathogenic in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-30). Associated with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures.

IRF2BPL p.Phe64fs

Q: What condition is associated with IRF2BPL p.Phe64fs (c.188_191dup)?

IRF2BPL p.Phe64fs (c.188_191dup) 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.188_191dup · VCV4879587

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 3.7	GERP 1.2, phastCons 1

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

Variant & gene context

Gene: IRF2BPL
Protein: p.Phe64fs
Coding: c.188_191dup
MANE Select: NM_024496
Type: Duplication
Location: chr14:77027601 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB

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.Asn197fs Likely pathogenic ★ same condition
IRF2BPL p.Pro332fs Likely pathogenic ★ same condition
IRF2BPL p.Thr237fs Likely pathogenic ★ same condition
IRF2BPL p.Thr425fs Likely pathogenic ★ same condition
IRF2BPL p.Gln105fs Uncertain significance ★ same condition
IRF2BPL p.Trp569Ter Pathogenic same condition
IRF2BPL p.Ala101fs Likely pathogenic ★★ same condition
IRF2BPL p.Arg188Ter Pathogenic/Likely 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-phe64fs (accessed [today's date]).

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