Is BIN3 p.Leu31Pro (c.92T>C) pathogenic?

BIN3 p.Leu31Pro (c.92T>C) is classified Uncertain significance in BIN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-09). AlphaMissense: likely pathogenic (0.9978); Rare (popmax 0.149%, mid).

How common is BIN3 p.Leu31Pro (c.92T>C) in the general population?

BIN3 p.Leu31Pro (c.92T>C) is rare (popmax 0.149%, mid) (gnomAD).

What do computational predictors say about BIN3 p.Leu31Pro (c.92T>C)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

BIN3 p.Leu31Pro

c.92T>C · rs200762212 · VCV2276750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic · top 1% in BIN3
REVEL	0.691	pathogenic-leaning
SaProt	LLR -14.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.041 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.149% Middle Eastern · 9/6,060 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.029% 467/1,613,044 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.149%	673
Finnishnot grpmax-eligible	0.0516%	1,939
European (non-Finnish)	0.031%	3,230
Remaining individualsnot grpmax-eligible	0.0304%	3,287
African / African-American	0.028%	3,572
Admixed American	0.0217%	4,616
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
South Asian	0.00439%	22,767

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: BIN3
Protein: p.Leu31Pro
Coding: c.92T>C
MANE Select: NM_018688
dbSNP: rs200762212
Type: single nucleotide variant
Location: chr8:22636928 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.83
Residue 31: the bar domain

Full BIN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BIN3 c.297+5C>T Benign ★★ same type
BIN3 p.Ala131Pro Uncertain significance ★ ⚠ same type
BIN3 p.Arg128Gln Uncertain significance ★ ⚠ same type
BIN3 p.Arg128Trp Uncertain significance ★ ⚠ same type
BIN3 p.Arg136Gly Uncertain significance ★ ⚠ same type
BIN3 p.Arg166Gln Uncertain significance ★ ⚠ same type
BIN3 p.Arg185Cys Uncertain significance ★ ⚠ same type
BIN3 p.Arg203Gln Uncertain significance ★ ⚠ same type

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/bin3-p-leu31pro (accessed [today's date]).

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