Is BIN1 p.Pro431Leu (c.1292C>T) pathogenic?

BIN1 p.Pro431Leu (c.1292C>T) is classified Benign/Likely benign in BIN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-06). AlphaMissense: likely benign (0.0758); Low-frequency (popmax 1.72%, eas); Associated with myopathy, centronuclear, 2.

What condition is associated with BIN1 p.Pro431Leu (c.1292C>T)?

BIN1 p.Pro431Leu (c.1292C>T) is associated with myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Pro431Leu (c.1292C>T) in the general population?

BIN1 p.Pro431Leu (c.1292C>T) is low-frequency (popmax 1.72%, eas) (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.Pro431Leu (c.1292C>T)?

AlphaMissense predicts likely benign (score 0.0758) — an in-silico prediction, not a clinical call.

BIN1 p.Pro431Leu

c.1292C>T · rs141119288 · VCV262473

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0758 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.72%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myopathy, centronuclear, 2

Computational evidence

Protein change
AlphaMissense	0.0758	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -7.69	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 8.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 58 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	24.7	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 1.72% East Asian · 752/43,714 alleles

Filtering AF 1.62% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.58%

Overall 0.0512% 813/1,587,120 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.72%	58
Remaining individualsnot grpmax-eligible	0.0538%	1,860
Middle Eastern	0.0175%	5,728
South Asian	0.00344%	29,039
European (non-Finnish)	0.00197%	50,748
Admixed American	0.00177%	56,462

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.Pro431Leu
Coding: c.1292C>T
MANE Select: NM_139343
dbSNP: rs141119288
Type: single nucleotide variant
Location: chr2:127052334 (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 431: 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.Pro431Ser 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-pro431leu (accessed [today's date]).

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