Is BEND3 p.Ser181Arg (c.541A>C) pathogenic?

BEND3 p.Ser181Arg (c.541A>C) is classified Uncertain significance in BEND3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-09). AlphaMissense: ambiguous (0.3907); Ultra-rare (popmax 0.0439%, sas).

How common is BEND3 p.Ser181Arg (c.541A>C) in the general population?

BEND3 p.Ser181Arg (c.541A>C) is ultra-rare (popmax 0.0439%, sas) (gnomAD).

What do computational predictors say about BEND3 p.Ser181Arg (c.541A>C)?

AlphaMissense predicts ambiguous (score 0.3907) — an in-silico prediction, not a clinical call.

BEND3 p.Ser181Arg

c.541A>C · rs781815701 · VCV2210145

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3907 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0439%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3907	ambiguous
REVEL	0.016	strongly benign-leaning
SaProt	LLR -7.33	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -3.6
Regional constraint	o/e 0.82	unconstrained · MANE · 30 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	1.966	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 0.0439% South Asian · 40/91,020 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.0026% 42/1,612,354 alleles · ultra-rare exomes 38/1,460,164 · genomes 4/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0439%	2,275
Remaining individualsnot grpmax-eligible	0.00321%	31,171

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.Ser181Arg
Coding: c.541A>C
MANE Select: NM_001367314
dbSNP: rs781815701
Type: single nucleotide variant
Location: chr6:107070650 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.11 · 2 PDB
Residue 181: the 'disordered' region

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-ser181arg (accessed [today's date]).

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