Is BEND2 p.Pro721Ser (c.2161C>T) pathogenic?

BEND2 p.Pro721Ser (c.2161C>T) is classified Uncertain significance in BEND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.1609); Ultra-rare (popmax 0.0741%, amr).

How common is BEND2 p.Pro721Ser (c.2161C>T) in the general population?

BEND2 p.Pro721Ser (c.2161C>T) is ultra-rare (popmax 0.0741%, amr) (gnomAD).

What do computational predictors say about BEND2 p.Pro721Ser (c.2161C>T)?

AlphaMissense predicts likely benign (score 0.1609) — an in-silico prediction, not a clinical call.

BEND2 p.Pro721Ser

c.2161C>T · VCV4645722

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1609 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0741%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1609	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.98	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 -4.1	GERP -3.5
Regional constraint	o/e 0.59	unconstrained · MANE · 6,046 bp · p 0.00055 · regional, not allelic
Overall
CADD	0.002	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 0.0741% Admixed American · 34/45,857 alleles

Filtering AF 0.0545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0477%

Overall 0.00405% 49/1,208,751 alleles · ultra-rare exomes 22/1,096,130 · genomes 27/112,621 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0741%	1,349
Remaining individualsnot grpmax-eligible	0.0189%	5,286
African / African-American	0.0105%	9,567

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: BEND2
Protein: p.Pro721Ser
Coding: c.2161C>T
MANE Select: NM_153346
Type: single nucleotide variant
Location: chrX:18171025 (GRCh38)
Structure: AlphaFold pLDDT 49.94
Residue 721: the ben 2 domain

Full BEND2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BEND2 p.Gln198His Benign ★★ same type
BEND2 p.Gly580Val Benign ★★ same type
BEND2 p.Ser183Ile Benign ★★ same type
BEND2 p.Thr367= Likely benign ★★ same type
BEND2 p.Val261Gly Benign ★★ same type
BEND2 p.Ala185Gly Uncertain significance ★ ⚠ same type
BEND2 p.Ala193Thr Uncertain significance ★ ⚠ same type
BEND2 p.Ala222Ser 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/bend2-p-pro721ser (accessed [today's date]).

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