Is IRF2BPL p.Pro372Arg (c.1115C>G) pathogenic?

IRF2BPL p.Pro372Arg (c.1115C>G) is classified Pathogenic in IRF2BPL (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-12-20). AlphaMissense: likely pathogenic (0.9952); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures.

How common is IRF2BPL p.Pro372Arg (c.1115C>G) in the general population?

IRF2BPL p.Pro372Arg (c.1115C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IRF2BPL p.Pro372Arg (c.1115C>G)?

AlphaMissense predicts likely pathogenic (score 0.9952) — an in-silico prediction, not a clinical call.

IRF2BPL p.Pro372Arg

Q: What condition is associated with IRF2BPL p.Pro372Arg (c.1115C>G)?

IRF2BPL p.Pro372Arg (c.1115C>G) 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.1115C>G · rs1555377336 · VCV559611

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9952 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9952	likely pathogenic ✓ concordant with ClinVar
REVEL	0.276	benign-leaning
SaProt	LLR -13.24	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	29.1	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: IRF2BPL
Protein: p.Pro372Arg
Coding: c.1115C>G
MANE Select: NM_024496
dbSNP: rs1555377336
Type: single nucleotide variant
Location: chr14:77026678 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 372: a UniProt-annotated variant site (in nedamss); a UniProt-annotated variant site (in nedamss; loss of function); a UniProt-annotated variant site (in nedamss; uncertain significance; no effect on 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.Pro372Ala Likely pathogenic ★ ⚠ same residue
IRF2BPL p.Arg188Ter Pathogenic/Likely pathogenic ★★ same condition
IRF2BPL p.Gln117Ter Likely pathogenic ★★ same condition
IRF2BPL p.Gln120Ter Pathogenic/Likely pathogenic ★★ same condition
IRF2BPL p.Gln121Ter Pathogenic/Likely pathogenic ★★ same condition
IRF2BPL p.Gln167Ter Pathogenic/Likely pathogenic ★★ same condition
IRF2BPL p.Gln497Ter Pathogenic/Likely pathogenic ★★ same condition
IRF2BPL p.Gln565Ter 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-pro372arg (accessed [today's date]).

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