Is IRF2BPL p.Phe420Leu (c.1260C>A) pathogenic?

IRF2BPL p.Phe420Leu (c.1260C>A) is classified Uncertain significance in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1.

How common is IRF2BPL p.Phe420Leu (c.1260C>A) in the general population?

IRF2BPL p.Phe420Leu (c.1260C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IRF2BPL p.Phe420Leu (c.1260C>A)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

IRF2BPL p.Phe420Leu

c.1260C>A · VCV3375987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 6% in IRF2BPL
REVEL	0.18	moderately benign-leaning
SaProt	LLR -10.93	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 2.4	GERP 0.35, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	23.8	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.Phe420Leu
Coding: c.1260C>A
MANE Select: NM_024496
Type: single nucleotide variant
Location: chr14:77026533 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 420: 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

Similar variants

IRF2BPL p.Phe420Ser Likely pathogenic ★ same residue
IRF2BPL p.Arg188Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln117Ter Likely pathogenic ★★ same type
IRF2BPL p.Gln119Ter Likely pathogenic ★★ same type
IRF2BPL p.Gln120Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln121Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln122Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln167Ter Pathogenic/Likely pathogenic ★★ 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/irf2bpl-p-phe420leu (accessed [today's date]).

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