Is BIN2 p.Arg142Trp (c.424C>T) pathogenic?

BIN2 p.Arg142Trp (c.424C>T) is classified Uncertain significance in BIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely pathogenic (0.9656); Very rare (popmax 0.00878%, sas).

How common is BIN2 p.Arg142Trp (c.424C>T) in the general population?

BIN2 p.Arg142Trp (c.424C>T) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about BIN2 p.Arg142Trp (c.424C>T)?

AlphaMissense predicts likely pathogenic (score 0.9656) — an in-silico prediction, not a clinical call.

BIN2 p.Arg142Trp

c.424C>T · VCV3260937

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9656	likely pathogenic · top 6% in BIN2
REVEL	0.735	pathogenic-leaning
SaProt	LLR -11.58	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 2.8	GERP -1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 43 kb · p 0.00047 · regional, not allelic
Overall
CADD	24.7	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 0.00878% South Asian · 8/91,076 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00328% 53/1,613,886 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,385
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00347%	28,780
African / African-American	0.00134%	74,896

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: BIN2
Protein: p.Arg142Trp
Coding: c.424C>T
MANE Select: NM_016293
Type: single nucleotide variant
Location: chr12:51299699 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.40 · 2 PDB
Residue 142: the bar domain; an α-helix

Full BIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BIN2 p.Ala121Val Uncertain significance ★ ⚠ same type
BIN2 p.Ala130Thr Uncertain significance ★ ⚠ same type
BIN2 p.Ala158Thr Uncertain significance ★ ⚠ same type
BIN2 p.Ala344Val Uncertain significance ★ ⚠ same type
BIN2 p.Ala384Thr Uncertain significance ★ ⚠ same type
BIN2 p.Arg123Lys Uncertain significance ★ ⚠ same type
BIN2 p.Arg138Thr Uncertain significance ★ ⚠ same type
BIN2 p.Arg202Cys 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/bin2-p-arg142trp (accessed [today's date]).

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