Is SETD2 p.Arg421Trp (c.1261A>T) pathogenic?

SETD2 p.Arg421Trp (c.1261A>T) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-21). AlphaMissense: ambiguous (0.5327); Very rare (popmax 0.00183%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg421Trp (c.1261A>T)?

SETD2 p.Arg421Trp (c.1261A>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg421Trp (c.1261A>T) in the general population?

SETD2 p.Arg421Trp (c.1261A>T) is very rare (popmax 0.00183%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Arg421Trp (c.1261A>T)?

AlphaMissense predicts ambiguous (score 0.5327) — an in-silico prediction, not a clinical call.

SETD2 p.Arg421Trp

c.1261A>T · rs1399084180 · VCV1805912

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5327 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00183%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.5327	ambiguous
REVEL	0.184	benign-leaning
SaProt	LLR -11.65	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00183% European (non-Finnish) · 21/1,146,984 alleles

Filtering AF 0.00118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000998%

Overall 0.00135% 21/1,551,578 alleles · very rare exomes 20/1,399,372 · genomes 1/152,206 · joint denominator

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: SETD2
Protein: p.Arg421Trp
Coding: c.1261A>T
MANE Select: NM_014159
dbSNP: rs1399084180
Type: single nucleotide variant
Location: chr3:47123375 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 421: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); the 'disordered' region

Full SETD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Luscan-Lumish syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD2 p.Arg421= Likely benign ★ same residue
SETD2 p.Arg1598Ter Pathogenic/Likely pathogenic ★★ same condition
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same condition
SETD2 p.Arg1740Trp Pathogenic/Likely pathogenic ★★ same condition
SETD2 p.Ala1121Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Ala679Val Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg1065Cys Uncertain significance ★★ same condition
SETD2 p.Arg329Gln Uncertain significance ★★ ⚠ 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/setd2-p-arg421trp (accessed [today's date]).

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