Is BIN1 p.Pro399Leu (c.1196C>T) pathogenic?

BIN1 p.Pro399Leu (c.1196C>T) is classified Uncertain significance in BIN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.0903); Ultra-rare (popmax 0.0112%, nfe); Associated with myopathy, centronuclear, 2.

What condition is associated with BIN1 p.Pro399Leu (c.1196C>T)?

BIN1 p.Pro399Leu (c.1196C>T) is associated with myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Pro399Leu (c.1196C>T) in the general population?

BIN1 p.Pro399Leu (c.1196C>T) is ultra-rare (popmax 0.0112%, nfe) (gnomAD).

How is Autosomal recessive centronuclear myopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BIN1 p.Pro399Leu (c.1196C>T)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

BIN1 p.Pro399Leu

c.1196C>T · rs558530329 · VCV593407

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myopathy, centronuclear, 2

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -5.91	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 5	GERP 0.86, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 58 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	25.2	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 0.0112% European (non-Finnish) · 128/1,147,136 alleles

Filtering AF 0.00954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.00876% 136/1,551,638 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0112%	8,962
Admixed American	0.00783%	12,770
Remaining individualsnot grpmax-eligible	0.00333%	30,054
East Asian	0.00244%	40,980
African / African-American	0.00137%	73,040

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.Pro399Leu
Coding: c.1196C>T
MANE Select: NM_139343
dbSNP: rs558530329
Type: single nucleotide variant
Location: chr2:127053948 (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 399: the 'clathrin-binding' region

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

Disease context

myopathy, centronuclear, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive centronuclear myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

BIN1 p.Pro399= Likely benign ★★ same residue
BIN1 p.Arg145Cys Likely pathogenic ★★ same condition
BIN1 p.Arg234Cys Pathogenic/Likely pathogenic ★★ same condition
BIN1 c.165+6T>C Uncertain significance ★★ same condition
BIN1 c.-163T>C Uncertain significance ★★ same condition
BIN1 p.Ala104Ser Uncertain significance ★★ ⚠ same condition
BIN1 p.Ala289Thr Uncertain significance ★★ ⚠ same condition
BIN1 p.Ala289Val 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-pro399leu (accessed [today's date]).

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