Is BIN1 p.Pro349Leu (c.1046C>T) pathogenic?

BIN1 p.Pro349Leu (c.1046C>T) is classified Uncertain significance in BIN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-02). AlphaMissense: ambiguous (0.5398); Very rare (popmax 0.00274%, afr); Associated with Inborn genetic diseases.

What condition is associated with BIN1 p.Pro349Leu (c.1046C>T)?

BIN1 p.Pro349Leu (c.1046C>T) is associated with Inborn genetic diseases, myopathy, centronuclear, 2 (ClinVar).

How common is BIN1 p.Pro349Leu (c.1046C>T) in the general population?

BIN1 p.Pro349Leu (c.1046C>T) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about BIN1 p.Pro349Leu (c.1046C>T)?

AlphaMissense predicts ambiguous (score 0.5398) — an in-silico prediction, not a clinical call.

BIN1 p.Pro349Leu

c.1046C>T · rs775494528 · VCV583021

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5398	ambiguous
REVEL	0.381	indeterminate
SaProt	LLR -10.07	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 58 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	29.0	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 0.00274% African / African-American · 2/72,904 alleles

Filtering AF 0.000455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000218%

Overall 0.000777% 12/1,543,428 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00274%	36,452
Admixed American	0.00198%	50,584
South Asian	0.0012%	83,290
European (non-Finnish)	0.000701%	142,671

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.Pro349Leu
Coding: c.1046C>T
MANE Select: NM_139343
dbSNP: rs775494528
Type: single nucleotide variant
Location: chr2:127057558 (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 349: the 'disordered' 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.Pro349= Conflicting classifications of pathogenicity ★ 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-pro349leu (accessed [today's date]).

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