Is SET p.Asp224Asn (c.670G>A) pathogenic?

SET p.Asp224Asn (c.670G>A) is classified Uncertain significance in SET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-04-16). AlphaMissense: likely pathogenic (0.9091); Very rare (popmax 8.54e-05%, nfe); Associated with intellectual disability, autosomal dominant 58.

What condition is associated with SET p.Asp224Asn (c.670G>A)?

SET p.Asp224Asn (c.670G>A) is associated with intellectual disability, autosomal dominant 58 (ClinVar).

How common is SET p.Asp224Asn (c.670G>A) in the general population?

SET p.Asp224Asn (c.670G>A) is very rare (popmax 8.54e-05%, nfe) (gnomAD).

What do computational predictors say about SET p.Asp224Asn (c.670G>A)?

AlphaMissense predicts likely pathogenic (score 0.9091) — an in-silico prediction, not a clinical call.

SET p.Asp224Asn

c.670G>A · rs2132255761 · VCV1211562

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.54e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 58

Computational evidence

Protein change
AlphaMissense	0.9091	likely pathogenic
REVEL	0.185	benign-leaning
SaProt	LLR -11.17	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 9.7	GERP 2, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 4,260 bp · p 5.8e-31 · regional, not allelic
Overall
CADD	25.1	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 D237N vs ClinVar D224N) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.54e-05% European (non-Finnish) · 1/1,171,212 alleles

Overall 6.91e-05% 1/1,447,150 alleles · very rare

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: SET
Protein: p.Asp224Asn
Coding: c.670G>A
MANE Select: NM_003011
dbSNP: rs2132255761
Type: single nucleotide variant
Location: chr9:128693902 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.62 · 3 PDB
Residue 224: the 'earmuff domain' region; an α-helix

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

Disease context

intellectual disability, autosomal dominant 58 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SET c.663+5G>C Pathogenic ★★ same condition
SET p.His105Tyr Likely pathogenic ★★ same condition
SET p.Asp260Glu Uncertain significance ★★ ⚠ same condition
SET p.Glu261Asp Uncertain significance ★★ ⚠ same condition
SET c.132-17C>T Benign ★★ same condition
SET c.493-14C>T Benign ★★ same condition
SET c.493-1G>A Pathogenic ★ same condition
SET p.Gln65Ter Likely pathogenic ★ same condition

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-asp224asn (accessed [today's date]).

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