Is BEND3 p.Arg426Ser (c.1276C>A) pathogenic?

BEND3 p.Arg426Ser (c.1276C>A) is classified Uncertain significance in BEND3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-25). AlphaMissense: ambiguous (0.5322); Very rare (popmax 0.00186%, nfe).

How common is BEND3 p.Arg426Ser (c.1276C>A) in the general population?

BEND3 p.Arg426Ser (c.1276C>A) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about BEND3 p.Arg426Ser (c.1276C>A)?

AlphaMissense predicts ambiguous (score 0.5322) — an in-silico prediction, not a clinical call.

BEND3 p.Arg426Ser

c.1276C>A · rs781871218 · VCV2520429

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5322 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5322	ambiguous
REVEL	0.137	moderately benign-leaning
SaProt	LLR -5.78	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 7.3	GERP -0.17, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 30 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	19.96	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 0.00186% European (non-Finnish) · 22/1,180,022 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00143% 23/1,613,770 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,637
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Arg426Ser
Coding: c.1276C>A
MANE Select: NM_001367314
dbSNP: rs781871218
Type: single nucleotide variant
Location: chr6:107069915 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 2 PDB
Residue 426: the ben 2 domain

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

Similar variants

BEND3 p.Arg426Cys 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-arg426ser (accessed [today's date]).

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