Is SET p.Lys141Arg (c.422A>G) pathogenic?

SET p.Lys141Arg (c.422A>G) is classified Uncertain significance in SET (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-16). AlphaMissense: likely pathogenic (0.8882); Very rare (popmax 0.00167%, amr); Associated with intellectual disability, autosomal dominant 58.

What condition is associated with SET p.Lys141Arg (c.422A>G)?

SET p.Lys141Arg (c.422A>G) is associated with intellectual disability, autosomal dominant 58 (ClinVar).

How common is SET p.Lys141Arg (c.422A>G) in the general population?

SET p.Lys141Arg (c.422A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SET p.Lys141Arg (c.422A>G)?

AlphaMissense predicts likely pathogenic (score 0.8882) — an in-silico prediction, not a clinical call.

SET p.Lys141Arg

c.422A>G · VCV3899875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 58

Computational evidence

Protein change
AlphaMissense	0.8882	likely pathogenic
REVEL	0.656	pathogenic-leaning
SaProt	LLR -13.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.79 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 4,260 bp · p 5.8e-31 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K154R vs ClinVar K141R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,906 alleles

Overall 6.88e-05% 1/1,453,966 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.Lys141Arg
Coding: c.422A>G
MANE Select: NM_003011
Type: single nucleotide variant
Location: chr9:128692911 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.62 · 3 PDB
Residue 141: a β-strand; the 'earmuff domain' region

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 p.Lys141fs Likely pathogenic same residue
SET c.663+5G>C Pathogenic ★★ same condition
SET p.His105Tyr Likely pathogenic ★★ same condition
SET p.Asp224Asn Uncertain significance ★★ ⚠ 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

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-lys141arg (accessed [today's date]).

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