Is IREB2 p.Thr751= (c.2253A>G) pathogenic?

IREB2 p.Thr751= (c.2253A>G) is classified Likely benign in IREB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). Very rare (popmax 0.00267%, afr).

How common is IREB2 p.Thr751= (c.2253A>G) in the general population?

IREB2 p.Thr751= (c.2253A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

IREB2 p.Thr751=

c.2253A>G · rs772696033 · VCV1977697

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -10	GERP -5.5
Overall
CADD	0.186	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,936 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000929% 15/1,613,898 alleles · very rare exomes 11/1,461,652 · genomes 4/152,246 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921
Remaining individualsnot grpmax-eligible	0.0048%	20,826
African / African-Americangrpmax	0.00267%	37,468
European (non-Finnish)	0.000424%	235,972

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: IREB2
Protein: p.Thr751=
Coding: c.2253A>G
MANE Select: NM_004136
dbSNP: rs772696033
Type: single nucleotide variant
Location: chr15:78490690 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.11 · 1 PDB
Residue 751: a UniProt-annotated variant site (in ndcama; may drastically decrease protein expression level)

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

Similar variants

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
IREB2 p.His22Leu 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-thr751 (accessed [today's date]).

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