Is BIN3 p.Arg245Trp (c.733C>T) pathogenic?

BIN3 p.Arg245Trp (c.733C>T) is classified Uncertain significance in BIN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.8051); Ultra-rare (popmax 0.06%, amr).

How common is BIN3 p.Arg245Trp (c.733C>T) in the general population?

BIN3 p.Arg245Trp (c.733C>T) is ultra-rare (popmax 0.06%, amr) (gnomAD).

What do computational predictors say about BIN3 p.Arg245Trp (c.733C>T)?

AlphaMissense predicts likely pathogenic (score 0.8051) — an in-silico prediction, not a clinical call.

BIN3 p.Arg245Trp

c.733C>T · VCV3991505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8051 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8051	likely pathogenic
REVEL	0.44	indeterminate
SaProt	LLR -13.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -3.2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.041 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.06% Admixed American · 36/59,972 alleles

Filtering AF 0.0445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0392%

Overall 0.00229% 37/1,613,526 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.06%	1,666
Remaining individualsnot grpmax-eligible	0.0016%	62,448

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: BIN3
Protein: p.Arg245Trp
Coding: c.733C>T
MANE Select: NM_018688
Type: single nucleotide variant
Location: chr8:22621451 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.83

Full BIN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BIN3 c.297+5C>T Benign ★★ same type
BIN3 p.Ala131Pro Uncertain significance ★ ⚠ same type
BIN3 p.Arg128Gln Uncertain significance ★ ⚠ same type
BIN3 p.Arg128Trp Uncertain significance ★ ⚠ same type
BIN3 p.Arg136Gly Uncertain significance ★ ⚠ same type
BIN3 p.Arg166Gln Uncertain significance ★ ⚠ same type
BIN3 p.Arg185Cys Uncertain significance ★ ⚠ same type
BIN3 p.Arg203Gln 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/bin3-p-arg245trp (accessed [today's date]).

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