Is IRF2BP2 p.Pro22= (c.66C>T) pathogenic?

IRF2BP2 p.Pro22= (c.66C>T) is classified Likely benign in IRF2BP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-02). Very rare (popmax 0.00426%, afr).

How common is IRF2BP2 p.Pro22= (c.66C>T) in the general population?

IRF2BP2 p.Pro22= (c.66C>T) is very rare (popmax 0.00426%, afr) (gnomAD).

IRF2BP2 p.Pro22=

c.66C>T · rs756025089 · VCV1907365

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00426%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -2.3, phastCons 0.91
Overall
CADD	14.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00426% African / African-American · 3/70,462 alleles

Filtering AF 0.00113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000613%

Overall 0.000706% 11/1,559,010 alleles · very rare exomes 9/1,407,646 · genomes 2/151,364 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00426%	23,487
East Asian	0.0026%	38,458
South Asian	0.00234%	42,824
European (non-Finnish)	0.000433%	231,063

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.Pro22=
Coding: c.66C>T
MANE Select: NM_182972
dbSNP: rs756025089
Type: single nucleotide variant
Location: chr1:234609429 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 56.84 · 3 PDB

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

Similar variants

IRF2BP2 p.Pro22Leu 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-pro22 (accessed [today's date]).

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