Is IREB2 p.Arg960Gln (c.2879G>A) pathogenic?

IREB2 p.Arg960Gln (c.2879G>A) is classified Uncertain significance in IREB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). AlphaMissense: likely benign (0.1816); Very rare (popmax 0.00138%, nfe); Associated with Inborn genetic diseases.

What condition is associated with IREB2 p.Arg960Gln (c.2879G>A)?

IREB2 p.Arg960Gln (c.2879G>A) is associated with Inborn genetic diseases (ClinVar).

How common is IREB2 p.Arg960Gln (c.2879G>A) in the general population?

IREB2 p.Arg960Gln (c.2879G>A) is very rare (popmax 0.00138%, nfe) (gnomAD).

What do computational predictors say about IREB2 p.Arg960Gln (c.2879G>A)?

AlphaMissense predicts likely benign (score 0.1816) — an in-silico prediction, not a clinical call.

IREB2 p.Arg960Gln

c.2879G>A · VCV4622201

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1816 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00138%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1816	likely benign
REVEL	0.422	indeterminate
SaProt	LLR -10.69	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 60 kb · p 2.8e-13 · regional, not allelic
Overall
CADD	29.8	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 0.00138% European (non-Finnish) · 16/1,157,650 alleles

Filtering AF 0.000818% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000662%

Overall 0.00113% 18/1,589,232 alleles · very rare exomes 15/1,437,100 · genomes 3/152,132 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00162%	61,600
European (non-Finnish)grpmax	0.00138%	72,353
South Asian	0.0011%	90,568

Remaining individuals 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.Arg960Gln
Coding: c.2879G>A
MANE Select: NM_004136
Type: single nucleotide variant
Location: chr15:78498130 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.11 · 1 PDB
Residue 960: a UniProt-annotated variant site (in ndcama; may drastically decrease protein expression level); an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IREB2 p.Ala534Thr Uncertain significance ★★ ⚠ same condition
IREB2 p.Arg697Trp Uncertain significance ★★ ⚠ same condition
IREB2 p.Asn925Thr Uncertain significance ★★ ⚠ same condition
IREB2 p.Cys53Tyr Uncertain significance ★★ same condition
IREB2 p.Glu917Lys Uncertain significance ★★ ⚠ same condition
IREB2 p.Gly184Asp Uncertain significance ★★ ⚠ same condition
IREB2 p.Gly656Ser Uncertain significance ★★ ⚠ same condition
IREB2 p.His22Leu Uncertain significance ★★ ⚠ same condition

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-arg960gln (accessed [today's date]).

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