Is BIN1 p.Pro491= (c.1473T>C) pathogenic?

BIN1 p.Pro491= (c.1473T>C) is classified Conflicting classifications of pathogenicity in BIN1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-08). Rare (popmax 0.196%, eas); Associated with myopathy, centronuclear, 2.

What condition is associated with BIN1 p.Pro491= (c.1473T>C)?

BIN1 p.Pro491= (c.1473T>C) is associated with myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Pro491= (c.1473T>C) in the general population?

BIN1 p.Pro491= (c.1473T>C) is rare (popmax 0.196%, eas) (gnomAD).

How is Autosomal recessive centronuclear myopathy inherited?

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

BIN1 p.Pro491=

c.1473T>C · rs779756862 · VCV331045

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.196%, eas)

Conditions

myopathy, centronuclear, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.2	GERP -4
Overall
CADD	5.246	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.196% East Asian · 88/44,880 alleles

Filtering AF 0.163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.00638% 103/1,613,964 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.196%	510
Remaining individualsnot grpmax-eligible	0.0112%	8,929
South Asian	0.00878%	11,384

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.Pro491=
Coding: c.1473T>C
MANE Select: NM_139343
dbSNP: rs779756862
Type: single nucleotide variant
Location: chr2:127050901 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.61 · 7 PDB

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.Pro491fs 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-pro491 (accessed [today's date]).

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