Is IRF2BP2 p.Pro424= (c.1272C>T) pathogenic?

IRF2BP2 p.Pro424= (c.1272C>T) is classified Likely benign in IRF2BP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). Very rare (popmax 0.005%, amr).

How common is IRF2BP2 p.Pro424= (c.1272C>T) in the general population?

IRF2BP2 p.Pro424= (c.1272C>T) is very rare (popmax 0.005%, amr) (gnomAD).

IRF2BP2 p.Pro424=

c.1272C>T · rs772478669 · VCV1589770

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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 0.66	GERP -0.33, phastCons 1
Overall
CADD	13.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,030 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00576% 93/1,614,232 alleles · very rare exomes 83/1,461,886 · genomes 10/152,346 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.111%	897
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed Americangrpmax	0.005%	20,010
European (non-Finnish)	0.00364%	27,443
African / African-American	0.00133%	75,064

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro424=
Coding: c.1272C>T
MANE Select: NM_182972
dbSNP: rs772478669
Type: single nucleotide variant
Location: chr1:234607629 (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.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
IRF2BP2 p.Ala502Ser 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-pro424 (accessed [today's date]).

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