IREB2 p.Pro704=
c.2112G>A · VCV4748596
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0332%, mid)
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 -3.1 | GERP -5.3 |
| Overall | ||
| CADD | 1.4 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0332%
Middle Eastern · 2/6,026 alleles
Filtering AF
0.00682%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00634%
Overall
0.00666%
107/1,606,916 alleles · ultra-rare
exomes 103/1,454,800 · genomes 4/152,116 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0332% | 3,013 |
| European (non-Finnish) | 0.00815% | 12,272 |
| Admixed American | 0.00518% | 19,301 |
| Remaining individualsnot grpmax-eligible | 0.00483% | 20,716 |
| African / African-American | 0.00269% | 37,148 |
| East Asian | 0.00223% | 44,848 |
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
- IREB2
- Protein
- p.Pro704=
- Coding
- c.2112G>A
- MANE Select
- NM_004136
- Type
- single nucleotide variant
- Location
- chr15:78490457 (GRCh38)
- Gene constraint
- LOEUF 0.389 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 87.11 · 1 PDB
- Residue 704
- a UniProt-annotated variant site (in ndcama; may drastically decrease protein expression level)
Similar variants
- IREB2 p.Pro704Leu Uncertain significance ★ ⚠ same residue
- IREB2 p.Ala534Thr Uncertain significance ★★ ⚠ same type
- IREB2 p.Arg697Trp Uncertain significance ★★ ⚠ same type
- IREB2 p.Asn925Thr Uncertain significance ★★ ⚠ same type
- IREB2 p.Cys53Tyr Uncertain significance ★★ same type
- IREB2 p.Glu917Lys Uncertain significance ★★ ⚠ same type
- IREB2 p.Gly184Asp Uncertain significance ★★ ⚠ same type
- IREB2 p.Gly656Ser 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/ireb2-p-pro704 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown