Is IRF2BP2 p.Pro264Ser (c.790C>T) pathogenic?

IRF2BP2 p.Pro264Ser (c.790C>T) is classified Uncertain significance in IRF2BP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-02). AlphaMissense: likely benign (0.0539); Very rare (popmax 0.000264%, nfe).

How common is IRF2BP2 p.Pro264Ser (c.790C>T) in the general population?

IRF2BP2 p.Pro264Ser (c.790C>T) is very rare (popmax 0.000264%, nfe) (gnomAD).

What do computational predictors say about IRF2BP2 p.Pro264Ser (c.790C>T)?

AlphaMissense predicts likely benign (score 0.0539) — an in-silico prediction, not a clinical call.

IRF2BP2 p.Pro264Ser

c.790C>T · rs1326230973 · VCV3016012

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0539 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000264%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0539	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 1.24	unconstrained · MANE · 2,107 bp · p 1.6e-10 · regional, not allelic
Overall
CADD	1.987	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000264% European (non-Finnish) · 3/1,136,296 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.0002% 3/1,503,056 alleles · very rare exomes 3/1,350,764 · genomes 0/152,292 · 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: IRF2BP2
Protein: p.Pro264Ser
Coding: c.790C>T
MANE Select: NM_182972
dbSNP: rs1326230973
Type: single nucleotide variant
Location: chr1:234608705 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 56.84 · 3 PDB
Residue 264: the 'disordered' region

Full IRF2BP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IRF2BP2 p.Pro264Leu Uncertain significance ★ ⚠ same residue
IRF2BP2 p.Ala143Gly Uncertain significance ★★ ⚠ same type
IRF2BP2 p.Ala209Gly Uncertain significance ★★ ⚠ same type
IRF2BP2 p.Ala214Thr Uncertain significance ★★ ⚠ same type
IRF2BP2 p.Ala246Val Uncertain significance ★★ ⚠ same type
IRF2BP2 p.Ala254Thr Uncertain significance ★★ ⚠ same type
IRF2BP2 p.Ala276Thr Uncertain significance ★★ ⚠ same type
IRF2BP2 p.Ala344Val 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/irf2bp2-p-pro264ser (accessed [today's date]).

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