Is BIN1 p.Ser462Leu (c.1385C>T) pathogenic?

BIN1 p.Ser462Leu (c.1385C>T) is classified Likely benign in BIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely benign (0.0741); Very rare (popmax 0.00401%, afr); Associated with myopathy, centronuclear, 2.

What condition is associated with BIN1 p.Ser462Leu (c.1385C>T)?

BIN1 p.Ser462Leu (c.1385C>T) is associated with myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Ser462Leu (c.1385C>T) in the general population?

BIN1 p.Ser462Leu (c.1385C>T) is very rare (popmax 0.00401%, 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.Ser462Leu (c.1385C>T)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

BIN1 p.Ser462Leu

c.1385C>T · rs200580275 · VCV461703

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myopathy, centronuclear, 2

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP -2.5, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 58 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	23.1	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 0.00401% African / African-American · 3/74,900 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.0136% 220/1,613,610 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.295%	339
Remaining individualsnot grpmax-eligible	0.0064%	15,619
African / African-Americangrpmax	0.00401%	24,967
European (non-Finnish)	0.00203%	49,165
South Asian	0.0011%	91,092

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser462Leu
Coding: c.1385C>T
MANE Select: NM_139343
dbSNP: rs200580275
Type: single nucleotide variant
Location: chr2:127051230 (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 462: 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.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
BIN1 p.Ala322Val 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-ser462leu (accessed [today's date]).

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