Is BIN1 p.Pro555Ser (c.1663C>T) pathogenic?

BIN1 p.Pro555Ser (c.1663C>T) is classified Uncertain significance in BIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-07). AlphaMissense: likely benign (0.2053); Very rare (popmax 0.00329%, sas); Associated with myopathy, centronuclear, 2.

What condition is associated with BIN1 p.Pro555Ser (c.1663C>T)?

BIN1 p.Pro555Ser (c.1663C>T) is associated with myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Pro555Ser (c.1663C>T) in the general population?

BIN1 p.Pro555Ser (c.1663C>T) is very rare (popmax 0.00329%, sas) (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.Pro555Ser (c.1663C>T)?

AlphaMissense predicts likely benign (score 0.2053) — an in-silico prediction, not a clinical call.

BIN1 p.Pro555Ser

c.1663C>T · rs759786484 · VCV2918342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myopathy, centronuclear, 2

Computational evidence

Protein change
AlphaMissense	0.2053	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -10.54	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.99, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 58 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	26.5	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 0.00329% South Asian · 3/91,086 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,614,166 alleles · very rare exomes 4/1,461,846 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,362
African / African-American	0.00133%	75,052

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.Pro555Ser
Coding: c.1663C>T
MANE Select: NM_139343
dbSNP: rs759786484
Type: single nucleotide variant
Location: chr2:127050432 (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 555: the sh3 domain; 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.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-pro555ser (accessed [today's date]).

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