Is SET p.His196Arg (c.587A>G) pathogenic?

SET p.His196Arg (c.587A>G) is classified Uncertain significance in SET (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-22). AlphaMissense: likely pathogenic (0.966); Absent from gnomAD v4.1; Associated with SET-related disorder.

What condition is associated with SET p.His196Arg (c.587A>G)?

SET p.His196Arg (c.587A>G) is associated with SET-related disorder (ClinVar).

How common is SET p.His196Arg (c.587A>G) in the general population?

SET p.His196Arg (c.587A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SET p.His196Arg (c.587A>G)?

AlphaMissense predicts likely pathogenic (score 0.966) — an in-silico prediction, not a clinical call.

SET p.His196Arg

c.587A>G · rs2490440099 · VCV2631229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.966 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SET-related disorder

Computational evidence

Protein change
AlphaMissense	0.966	likely pathogenic
REVEL	0.266	benign-leaning
SaProt	LLR -14.60	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 4,260 bp · p 5.8e-31 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM H209R vs ClinVar H196R) — verify the residue.

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: SET
Protein: p.His196Arg
Coding: c.587A>G
MANE Select: NM_003011
dbSNP: rs2490440099
Type: single nucleotide variant
Location: chr9:128693732 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.62 · 3 PDB
Residue 209 UniProt numbering: the 'earmuff domain' region

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

Disease context

SET-related disorder

Similar variants

SET p.Gln39Ter Pathogenic ★ same condition
SET p.Asp202Gly Uncertain significance ⚠ same condition
SET p.Ser197= Likely benign same condition
SET p.Asp247del Uncertain significance same condition
SET c.664-5_664-4del Likely benign same condition
SET c.663+5G>C Pathogenic ★★ same type
SET p.His105Tyr Likely pathogenic ★★ same type
SET p.Asp224Asn 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/set-p-his196arg (accessed [today's date]).

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