Is BIN1 p.Arg66Trp (c.196C>T) pathogenic?

BIN1 p.Arg66Trp (c.196C>T) is classified Uncertain significance in BIN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.9209); Very rare (popmax 0.00892%, eas); Associated with Inborn genetic diseases.

What condition is associated with BIN1 p.Arg66Trp (c.196C>T)?

BIN1 p.Arg66Trp (c.196C>T) is associated with Inborn genetic diseases, myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Arg66Trp (c.196C>T) in the general population?

BIN1 p.Arg66Trp (c.196C>T) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about BIN1 p.Arg66Trp (c.196C>T)?

AlphaMissense predicts likely pathogenic (score 0.9209) — an in-silico prediction, not a clinical call.

BIN1 p.Arg66Trp

c.196C>T · rs767159511 · VCV2688670

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9209	likely pathogenic
REVEL	0.177	moderately benign-leaning
SaProt	LLR -15.72	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 3.5	GERP -1.4, 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 0.00892% East Asian · 4/44,850 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00155% 25/1,613,094 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,212
African / African-American	0.00534%	18,715
Remaining individualsnot grpmax-eligible	0.00481%	20,804
South Asian	0.00329%	30,349
Admixed American	0.00167%	59,998
European (non-Finnish)	0.000847%	117,999

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.Arg66Trp
Coding: c.196C>T
MANE Select: NM_139343
dbSNP: rs767159511
Type: single nucleotide variant
Location: chr2:127070786 (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 66: the bar domain; an α-helix; the 'interaction with bin2' region

Full BIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myopathy, centronuclear, 2

Similar variants

BIN1 p.Arg66Gln 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-arg66trp (accessed [today's date]).

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