Is BEND2 p.Arg588His (c.1763G>A) pathogenic?

BEND2 p.Arg588His (c.1763G>A) is classified Uncertain significance in BEND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.1016); Ultra-rare (popmax 0.0177%, sas).

How common is BEND2 p.Arg588His (c.1763G>A) in the general population?

BEND2 p.Arg588His (c.1763G>A) is ultra-rare (popmax 0.0177%, sas) (gnomAD).

What do computational predictors say about BEND2 p.Arg588His (c.1763G>A)?

AlphaMissense predicts likely benign (score 0.1016) — an in-silico prediction, not a clinical call.

BEND2 p.Arg588His

c.1763G>A · rs751032537 · VCV2603464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1016 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1016	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -8.12	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 -2.3	GERP -2.9
Regional constraint	o/e 1.00	unconstrained · MANE · 50 kb · p 0.98 · regional, not allelic
Overall
CADD	0.072	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 0.0177% South Asian · 10/56,491 alleles

Filtering AF 0.00952% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00729%

Overall 0.00282% 34/1,207,059 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0177%	5,649
Admixed American	0.00438%	22,809
European (non-Finnish)	0.00235%	42,525
Remaining individualsnot grpmax-eligible	0.00211%	47,496

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: BEND2
Protein: p.Arg588His
Coding: c.1763G>A
MANE Select: NM_153346
dbSNP: rs751032537
Type: single nucleotide variant
Location: chrX:18174248 (GRCh38)
Structure: AlphaFold pLDDT 49.94
Residue 588: the 'disordered' region

Full BEND2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BEND2 p.Arg588Cys Uncertain significance ★ ⚠ same residue
BEND2 p.Gln198His Benign ★★ same type
BEND2 p.Gly580Val Benign ★★ same type
BEND2 p.Ser183Ile Benign ★★ ⚠ same type
BEND2 p.Thr367= Likely benign ★★ same type
BEND2 p.Val261Gly Benign ★★ same type
BEND2 p.Ala185Gly Uncertain significance ★ ⚠ same type
BEND2 p.Ala193Thr 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/bend2-p-arg588his (accessed [today's date]).

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