Is BEND2 p.Pro673Leu (c.2018C>T) pathogenic?

BEND2 p.Pro673Leu (c.2018C>T) is classified Uncertain significance in BEND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: ambiguous (0.4744); Very rare (popmax 0.000448%, nfe).

How common is BEND2 p.Pro673Leu (c.2018C>T) in the general population?

BEND2 p.Pro673Leu (c.2018C>T) is very rare (popmax 0.000448%, nfe) (gnomAD).

What do computational predictors say about BEND2 p.Pro673Leu (c.2018C>T)?

AlphaMissense predicts ambiguous (score 0.4744) — an in-silico prediction, not a clinical call.

BEND2 p.Pro673Leu

c.2018C>T · rs776345809 · VCV2249251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000448%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4744	ambiguous · top 10% in BEND2
REVEL	0.272	benign-leaning
SaProt	LLR -6.72	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 3.5	GERP -3, phastCons 0.94
Regional constraint	o/e 1.00	unconstrained · MANE · 50 kb · p 0.98 · regional, not allelic
Overall
CADD	12.59	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 0.000448% European (non-Finnish) · 4/893,072 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000365% 4/1,095,428 alleles · very rare

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.Pro673Leu
Coding: c.2018C>T
MANE Select: NM_153346
dbSNP: rs776345809
Type: single nucleotide variant
Location: chrX:18171168 (GRCh38)
Structure: AlphaFold pLDDT 49.94
Residue 673: 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-pro673leu (accessed [today's date]).

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