Is INSYN2A p.His176Arg (c.527A>G) pathogenic?

INSYN2A p.His176Arg (c.527A>G) is classified Uncertain significance in INSYN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-14). AlphaMissense: likely benign (0.0858); Absent from gnomAD v4.1.

How common is INSYN2A p.His176Arg (c.527A>G) in the general population?

INSYN2A p.His176Arg (c.527A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about INSYN2A p.His176Arg (c.527A>G)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

INSYN2A p.His176Arg

c.527A>G · VCV3860729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -6.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.38	phastCons 0.071
Regional constraint	o/e 1.02	unconstrained · MANE · 1,029 bp · p 0.63 · regional, not allelic
Overall
CADD	12.66	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: INSYN2A
Protein: p.His176Arg
Coding: c.527A>G
MANE Select: NM_001290223 · reported on NM_001039762
Type: single nucleotide variant
Location: chr10:127175869 (GRCh38)

Full INSYN2A 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/insyn2a-p-his176arg (accessed [today's date]).

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