Is SET p.Glu261Asp (c.783A>T) pathogenic?

SET p.Glu261Asp (c.783A>T) is classified Uncertain significance in SET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-26). AlphaMissense: likely benign (0.0623); Very rare (popmax 0.00701%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SET p.Glu261Asp (c.783A>T)?

SET p.Glu261Asp (c.783A>T) is associated with Inborn genetic diseases, intellectual disability, autosomal dominant 58 (ClinVar).

How common is SET p.Glu261Asp (c.783A>T) in the general population?

SET p.Glu261Asp (c.783A>T) is very rare (popmax 0.00701%, nfe) (gnomAD).

What do computational predictors say about SET p.Glu261Asp (c.783A>T)?

AlphaMissense predicts likely benign (score 0.0623) — an in-silico prediction, not a clinical call.

SET p.Glu261Asp

c.783A>T · rs878926618 · VCV3160563

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00701%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0623	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP 1.3	GERP 0.015, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 756 bp · p 0.017 · regional, not allelic
Overall
CADD	18.83	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E274D vs ClinVar E261D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00701% European (non-Finnish) · 79/1,126,798 alleles

Filtering AF 0.00572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0053%

Overall 0.00604% 93/1,538,648 alleles · very rare exomes 85/1,386,754 · genomes 8/151,894 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0117%	8,531
European (non-Finnish)grpmax	0.00701%	14,263
South Asian	0.00583%	17,139
African / African-American	0.00274%	36,473

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu261Asp
Coding: c.783A>T
MANE Select: NM_003011
dbSNP: rs878926618
Type: single nucleotide variant
Location: chr9:128694015 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.62 · 3 PDB
Residue 274 UniProt numbering: a UniProt-annotated variant site (in mrd58); the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability, autosomal dominant 58

Similar variants

SET p.Glu261del Uncertain significance ★ 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 c.132-17C>T Benign ★★ same condition
SET c.493-14C>T Benign ★★ same condition
SET p.Asp235Glu Likely 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-glu261asp (accessed [today's date]).

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