Is BIN1 p.Arg145Cys (c.433C>T) pathogenic?

BIN1 p.Arg145Cys (c.433C>T) is classified Likely pathogenic in BIN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-03-10). AlphaMissense: likely pathogenic (0.9946); Ultra-rare (popmax 0.0165%, mid); Associated with myopathy, centronuclear, 2.

What condition is associated with BIN1 p.Arg145Cys (c.433C>T)?

BIN1 p.Arg145Cys (c.433C>T) is associated with myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Arg145Cys (c.433C>T) in the general population?

BIN1 p.Arg145Cys (c.433C>T) is ultra-rare (popmax 0.0165%, mid) (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.Arg145Cys (c.433C>T)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

BIN1 p.Arg145Cys

c.433C>T · rs1249621033 · VCV617682

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

myopathy, centronuclear, 2

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic ✓ concordant with ClinVar · top 9% in BIN1
REVEL	0.517	indeterminate
SaProt	LLR -15.29	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 4.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 58 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	28.2	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,076 alleles · ultra-rare exomes 5/1,461,774 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.000339%	295,001

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.Arg145Cys
Coding: c.433C>T
MANE Select: NM_139343
dbSNP: rs1249621033
Type: single nucleotide variant
Location: chr2:127069010 (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 145: the bar domain; a UniProt-annotated variant site (in cnm2); 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.Arg145His Uncertain significance ★ ⚠ same residue
BIN1 p.Arg145Ser Uncertain significance ★ ⚠ same residue
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-arg145cys (accessed [today's date]).

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