Is BEND4 p.Asn228Ser (c.683A>G) pathogenic?

BEND4 p.Asn228Ser (c.683A>G) is classified Uncertain significance in BEND4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: likely benign (0.0506); Ultra-rare (popmax 0.0559%, sas).

How common is BEND4 p.Asn228Ser (c.683A>G) in the general population?

BEND4 p.Asn228Ser (c.683A>G) is ultra-rare (popmax 0.0559%, sas) (gnomAD).

What do computational predictors say about BEND4 p.Asn228Ser (c.683A>G)?

AlphaMissense predicts likely benign (score 0.0506) — an in-silico prediction, not a clinical call.

BEND4 p.Asn228Ser

c.683A>G · VCV3480424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0506 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0559%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0506	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -5.21	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 -11	GERP -3.1
Regional constraint	o/e 1.01	unconstrained · MANE · 35 kb · p 0.85 · regional, not allelic
Overall
CADD	0.001	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 0.0559% South Asian · 50/89,508 alleles

Filtering AF 0.0434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0391%

Overall 0.00684% 110/1,607,260 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0559%	1,790
Admixed American	0.0319%	3,131
Middle Eastern	0.0166%	6,032
Remaining individualsnot grpmax-eligible	0.00964%	10,369
East Asian	0.00668%	14,960
African / African-American	0.00667%	14,988
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,968
European (non-Finnish)	0.00212%	47,063

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: BEND4
Protein: p.Asn228Ser
Coding: c.683A>G
MANE Select: NM_207406
Type: single nucleotide variant
Location: chr4:42143799 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.57

Full BEND4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BEND4 p.Gln224Glu Uncertain significance ★★ ⚠ same type
BEND4 p.Ser268Leu Uncertain significance ★★ ⚠ same type
BEND4 p.Pro473= Likely benign ★★ same type
BEND4 p.Ala125Thr Uncertain significance ★ ⚠ same type
BEND4 p.Ala244Pro Uncertain significance ★ ⚠ same type
BEND4 p.Ala518Pro Uncertain significance ★ ⚠ same type
BEND4 p.Ala66Val Uncertain significance ★ ⚠ same type
BEND4 p.Ala82Pro 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/bend4-p-asn228ser (accessed [today's date]).

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