Is IREB2 p.Ile245Val (c.733A>G) pathogenic?

IREB2 p.Ile245Val (c.733A>G) is classified Uncertain significance in IREB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-13). AlphaMissense: likely benign (0.084); Ultra-rare (popmax 0.0134%, amr).

How common is IREB2 p.Ile245Val (c.733A>G) in the general population?

IREB2 p.Ile245Val (c.733A>G) is ultra-rare (popmax 0.0134%, amr) (gnomAD).

What do computational predictors say about IREB2 p.Ile245Val (c.733A>G)?

AlphaMissense predicts likely benign (score 0.084) — an in-silico prediction, not a clinical call.

IREB2 p.Ile245Val

c.733A>G · rs191113858 · VCV2077748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.084 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.084	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -3.94	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 3.2	phastCons 0.98
Regional constraint	o/e 0.78	unconstrained · MANE · 60 kb · p 2.8e-13 · regional, not allelic
Overall
CADD	11.47	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 0.0134% Admixed American · 8/59,570 alleles

Filtering AF 0.00666% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00485%

Overall 0.000497% 8/1,610,992 alleles · ultra-rare exomes 7/1,458,678 · genomes 1/152,314 · 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: IREB2
Protein: p.Ile245Val
Coding: c.733A>G
MANE Select: NM_004136
dbSNP: rs191113858
Type: single nucleotide variant
Location: chr15:78471774 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.11 · 1 PDB
Residue 245: a β-strand

Full IREB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IREB2 p.Ile245Phe 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-ile245val (accessed [today's date]).

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