Is BIN1 p.Pro299Leu (c.896C>T) pathogenic?

BIN1 p.Pro299Leu (c.896C>T) is classified Uncertain significance in BIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: likely benign (0.0762); Very rare (popmax 8.54e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BIN1 p.Pro299Leu (c.896C>T)?

BIN1 p.Pro299Leu (c.896C>T) is associated with Inborn genetic diseases (ClinVar).

How common is BIN1 p.Pro299Leu (c.896C>T) in the general population?

BIN1 p.Pro299Leu (c.896C>T) is very rare (popmax 8.54e-05%, nfe) (gnomAD).

What do computational predictors say about BIN1 p.Pro299Leu (c.896C>T)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

BIN1 p.Pro299Leu

c.896C>T · rs1558811072 · VCV2309871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.54e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -6.84	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 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 58 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	26.2	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 8.54e-05% European (non-Finnish) · 1/1,170,980 alleles

Overall 6.94e-05% 1/1,441,430 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: BIN1
Protein: p.Pro299Leu
Coding: c.896C>T
MANE Select: NM_139343
dbSNP: rs1558811072
Type: single nucleotide variant
Location: chr2:127059117 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.61 · 7 PDB
Residue 299: the 'disordered' region

Full BIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BIN1 p.Ala380Thr Uncertain significance ★★ ⚠ same condition
BIN1 p.Ala465Val Uncertain significance ★★ ⚠ same condition
BIN1 p.Arg514His Uncertain significance ★★ ⚠ same condition
BIN1 p.Arg66Trp Uncertain significance ★★ ⚠ same condition
BIN1 p.Asp394Gly Uncertain significance ★★ ⚠ same condition
BIN1 p.Asp530Asn Uncertain significance ★★ same condition
BIN1 p.Asp570Glu Uncertain significance ★★ ⚠ same condition
BIN1 p.Asp93Tyr Uncertain significance ★★ same condition

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/bin1-p-pro299leu (accessed [today's date]).

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