Is IRF2BP2 p.Ser293Pro (c.877T>C) pathogenic?

IRF2BP2 p.Ser293Pro (c.877T>C) is classified Conflicting classifications of pathogenicity in IRF2BP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-21). AlphaMissense: likely benign (0.0523); Ultra-rare (popmax 0.0375%, afr).

How common is IRF2BP2 p.Ser293Pro (c.877T>C) in the general population?

IRF2BP2 p.Ser293Pro (c.877T>C) is ultra-rare (popmax 0.0375%, afr) (gnomAD).

What do computational predictors say about IRF2BP2 p.Ser293Pro (c.877T>C)?

AlphaMissense predicts likely benign (score 0.0523) — an in-silico prediction, not a clinical call.

IRF2BP2 p.Ser293Pro

c.877T>C · VCV3530000

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0523 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0375%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0523	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -5.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.59, phastCons 0.93
Regional constraint	o/e 1.24	unconstrained · MANE · 2,107 bp · p 1.6e-10 · regional, not allelic
Overall
CADD	16.64	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

Grpmax group 0.0375% African / African-American · 27/72,052 alleles

Filtering AF 0.0264% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0227%

Overall 0.00184% 29/1,574,866 alleles · ultra-rare exomes 10/1,422,812 · genomes 19/152,054 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0375%	2,669
Remaining individualsnot grpmax-eligible	0.00164%	60,826
South Asian	0.00115%	86,758

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.Ser293Pro
Coding: c.877T>C
MANE Select: NM_182972
Type: single nucleotide variant
Location: chr1:234608618 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 56.84 · 3 PDB
Residue 293: the 'disordered' region

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

Similar variants

IRF2BP2 p.Ser293Phe 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-ser293pro (accessed [today's date]).

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