Is BIN3 p.Ser2Cys (c.4A>T) pathogenic?

BIN3 p.Ser2Cys (c.4A>T) is classified Uncertain significance in BIN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely pathogenic (0.6142); Very rare (popmax 0.00565%, nfe).

How common is BIN3 p.Ser2Cys (c.4A>T) in the general population?

BIN3 p.Ser2Cys (c.4A>T) is very rare (popmax 0.00565%, nfe) (gnomAD).

What do computational predictors say about BIN3 p.Ser2Cys (c.4A>T)?

AlphaMissense predicts likely pathogenic (score 0.6142) — an in-silico prediction, not a clinical call.

BIN3 p.Ser2Cys

c.4A>T · VCV3824349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6142 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00565%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6142	likely pathogenic
REVEL	0.273	benign-leaning
SaProt	LLR -12.52	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.041 · regional, not allelic
Overall
CADD	29.1	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 0.00565% European (non-Finnish) · 66/1,168,910 alleles

Filtering AF 0.00455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00415%

Overall 0.00453% 72/1,590,108 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00565%	17,711
Remaining individualsnot grpmax-eligible	0.00488%	20,502
African / African-American	0.00403%	24,831

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.Ser2Cys
Coding: c.4A>T
MANE Select: NM_018688
Type: single nucleotide variant
Location: chr8:22669048 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.83

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-ser2cys (accessed [today's date]).

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