Is BIN1 p.Leu227= (c.681G>A) pathogenic?

BIN1 p.Leu227= (c.681G>A) is classified Conflicting classifications of pathogenicity in BIN1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-21). Ultra-rare (popmax 0.0433%, nfe); Associated with myopathy, centronuclear, 2.

What condition is associated with BIN1 p.Leu227= (c.681G>A)?

BIN1 p.Leu227= (c.681G>A) is associated with myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Leu227= (c.681G>A) in the general population?

BIN1 p.Leu227= (c.681G>A) is ultra-rare (popmax 0.0433%, nfe) (gnomAD).

How is Autosomal recessive centronuclear myopathy inherited?

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

BIN1 p.Leu227=

c.681G>A · rs199658397 · VCV331053

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, nfe)

Conditions

myopathy, centronuclear, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.46	GERP -3.2, phastCons 0.03
Overall
CADD	6.432	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0433% European (non-Finnish) · 511/1,179,988 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0389%

Overall 0.0327% 527/1,613,820 alleles · ultra-rare exomes 504/1,461,450 · genomes 23/152,370 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0433%	2,309
Remaining individualsnot grpmax-eligible	0.0176%	5,681
African / African-American	0.004%	25,021
Admixed American	0.00333%	30,018

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.Leu227=
Coding: c.681G>A
MANE Select: NM_139343
dbSNP: rs199658397
Type: single nucleotide variant
Location: chr2:127063950 (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 227: the bar domain; an α-helix

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.Leu227Val Uncertain significance ★★ ⚠ 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-leu227 (accessed [today's date]).

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