Is INSYN2B p.Ala96Glu (c.287C>A) pathogenic?

INSYN2B p.Ala96Glu (c.287C>A) is classified Uncertain significance in INSYN2B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-08). AlphaMissense: likely pathogenic (0.8702); Very rare (popmax 0.00137%, afr).

How common is INSYN2B p.Ala96Glu (c.287C>A) in the general population?

INSYN2B p.Ala96Glu (c.287C>A) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about INSYN2B p.Ala96Glu (c.287C>A)?

AlphaMissense predicts likely pathogenic (score 0.8702) — an in-silico prediction, not a clinical call.

INSYN2B p.Ala96Glu

c.287C>A · rs758663090 · VCV3110005

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8702	likely pathogenic
REVEL	0.179	moderately benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 0.43, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	23.3	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 0.00137% African / African-American · 1/73,018 alleles

Filtering AF 0.000254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000516% 8/1,551,476 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00137%	73,018
European (non-Finnish)	0.00061%	163,848

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: INSYN2B
Protein: p.Ala96Glu
Coding: c.287C>A
MANE Select: NM_004946 · reported on NM_001129891
dbSNP: rs758663090
Type: single nucleotide variant
Location: chr5:169883612 (GRCh38)

Full INSYN2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/insyn2b-p-ala96glu (accessed [today's date]).

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