Is BEND3 p.Arg76Trp (c.226C>T) pathogenic?

BEND3 p.Arg76Trp (c.226C>T) is classified Uncertain significance in BEND3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: ambiguous (0.4792); Very rare (popmax 0.00167%, amr).

How common is BEND3 p.Arg76Trp (c.226C>T) in the general population?

BEND3 p.Arg76Trp (c.226C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BEND3 p.Arg76Trp (c.226C>T)?

AlphaMissense predicts ambiguous (score 0.4792) — an in-silico prediction, not a clinical call.

BEND3 p.Arg76Trp

c.226C>T · rs374883376 · VCV3133687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4792	ambiguous
REVEL	0.255	benign-leaning
SaProt	LLR -9.93	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 30 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	29.4	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 0.00167% Admixed American · 1/59,980 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00124% 20/1,612,574 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,980
Finnishnot grpmax-eligible	0.00158%	63,174
European (non-Finnish)	0.00144%	69,413
South Asian	0.0011%	91,046

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: BEND3
Protein: p.Arg76Trp
Coding: c.226C>T
MANE Select: NM_001367314
dbSNP: rs374883376
Type: single nucleotide variant
Location: chr6:107098565 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 2 PDB

Full BEND3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BEND3 p.Arg76Gln Uncertain significance ★ ⚠ same residue
BEND3 p.Ala102Val Uncertain significance ★ ⚠ same type
BEND3 p.Ala122Gly Uncertain significance ★ ⚠ same type
BEND3 p.Ala161Thr Uncertain significance ★ ⚠ same type
BEND3 p.Ala250Val Uncertain significance ★ ⚠ same type
BEND3 p.Ala251Thr Uncertain significance ★ ⚠ same type
BEND3 p.Ala28Asp Uncertain significance ★ ⚠ same type
BEND3 p.Ala355Thr 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/bend3-p-arg76trp (accessed [today's date]).

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