Is BIN1 p.Arg336Trp (c.1006C>T) pathogenic?

BIN1 p.Arg336Trp (c.1006C>T) is classified Uncertain significance in BIN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-10). AlphaMissense: likely pathogenic (0.8346); Ultra-rare (popmax 0.04%, afr); Associated with myopathy, centronuclear, 2.

What condition is associated with BIN1 p.Arg336Trp (c.1006C>T)?

BIN1 p.Arg336Trp (c.1006C>T) is associated with myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Arg336Trp (c.1006C>T) in the general population?

BIN1 p.Arg336Trp (c.1006C>T) is ultra-rare (popmax 0.04%, afr) (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.Arg336Trp (c.1006C>T)?

AlphaMissense predicts likely pathogenic (score 0.8346) — an in-silico prediction, not a clinical call.

BIN1 p.Arg336Trp

c.1006C>T · rs76037557 · VCV1302671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8346 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myopathy, centronuclear, 2

Computational evidence

Protein change
AlphaMissense	0.8346	likely pathogenic
REVEL	0.206	benign-leaning
SaProt	LLR -13.42	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 58 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	33.0	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 0.04% African / African-American · 29/72,538 alleles

Filtering AF 0.0286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0247%

Overall 0.00373% 57/1,526,658 alleles · ultra-rare exomes 36/1,374,514 · genomes 21/152,144 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,501
South Asian	0.011%	9,101
East Asian	0.00248%	40,278
Finnishnot grpmax-eligible	0.00169%	59,170
European (non-Finnish)	0.0015%	66,528

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.Arg336Trp
Coding: c.1006C>T
MANE Select: NM_139343
dbSNP: rs76037557
Type: single nucleotide variant
Location: chr2:127057598 (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 336: the 'disordered' 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.Arg336Gln 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-arg336trp (accessed [today's date]).

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