Is BIN3 p.Ala131Pro (c.391G>C) pathogenic?

BIN3 p.Ala131Pro (c.391G>C) is classified Uncertain significance in BIN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). AlphaMissense: likely pathogenic (0.9946); Very rare (popmax 0.00992%, nfe).

How common is BIN3 p.Ala131Pro (c.391G>C) in the general population?

BIN3 p.Ala131Pro (c.391G>C) is very rare (popmax 0.00992%, nfe) (gnomAD).

What do computational predictors say about BIN3 p.Ala131Pro (c.391G>C)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

BIN3 p.Ala131Pro

c.391G>C · rs377437801 · VCV2359369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00992%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic · top 4% in BIN3
REVEL	0.291	indeterminate
SaProt	LLR -12.28	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.041 · regional, not allelic
Overall
CADD	24.9	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 0.00992% European (non-Finnish) · 117/1,179,814 alleles

Filtering AF 0.00843% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00787%

Overall 0.00812% 131/1,613,720 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00992%	10,084
African / African-American	0.00801%	12,490
Admixed American	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.0048%	20,821
Finnishnot grpmax-eligible	0.00313%	31,965

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.Ala131Pro
Coding: c.391G>C
MANE Select: NM_018688
dbSNP: rs377437801
Type: single nucleotide variant
Location: chr8:22624311 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.83
Residue 131: 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.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
BIN3 p.Arg233Trp 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-ala131pro (accessed [today's date]).

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