Is BIN2 p.Phe247Ser (c.740T>C) pathogenic?

BIN2 p.Phe247Ser (c.740T>C) is classified Uncertain significance in BIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely pathogenic (0.964); Ultra-rare (popmax 0.0198%, sas).

How common is BIN2 p.Phe247Ser (c.740T>C) in the general population?

BIN2 p.Phe247Ser (c.740T>C) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about BIN2 p.Phe247Ser (c.740T>C)?

AlphaMissense predicts likely pathogenic (score 0.964) — an in-silico prediction, not a clinical call.

BIN2 p.Phe247Ser

c.740T>C · rs780678634 · VCV2517907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.964 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.964	likely pathogenic · top 6% in BIN2
REVEL	0.77	pathogenic-leaning
SaProt	LLR -11.37	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 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 43 kb · p 0.00047 · regional, not allelic
Overall
CADD	26.8	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 0.0198% South Asian · 18/91,042 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.0013% 21/1,612,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,058
Remaining individualsnot grpmax-eligible	0.00481%	20,807

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.Phe247Ser
Coding: c.740T>C
MANE Select: NM_016293
dbSNP: rs780678634
Type: single nucleotide variant
Location: chr12:51295817 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.40 · 2 PDB

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.Arg142Trp 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-phe247ser (accessed [today's date]).

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