Is BEND3 p.Glu421Lys (c.1261G>A) pathogenic?

BEND3 p.Glu421Lys (c.1261G>A) is classified Uncertain significance in BEND3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely pathogenic (0.9103); Very rare (popmax 0.00333%, amr).

How common is BEND3 p.Glu421Lys (c.1261G>A) in the general population?

BEND3 p.Glu421Lys (c.1261G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about BEND3 p.Glu421Lys (c.1261G>A)?

AlphaMissense predicts likely pathogenic (score 0.9103) — an in-silico prediction, not a clinical call.

BEND3 p.Glu421Lys

c.1261G>A · VCV3991284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9103 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9103	likely pathogenic
REVEL	0.427	indeterminate
SaProt	LLR -10.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 30 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.0026% 42/1,613,674 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
European (non-Finnish)	0.00288%	34,706
African / African-American	0.00267%	37,439
South Asian	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,476
Finnishnot grpmax-eligible	0.00157%	63,742

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.Glu421Lys
Coding: c.1261G>A
MANE Select: NM_001367314
Type: single nucleotide variant
Location: chr6:107069930 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 2 PDB
Residue 421: the ben 2 domain

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

Similar variants

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
BEND3 p.Ala387Thr 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-glu421lys (accessed [today's date]).

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