Is SETD2 p.Arg402Trp (c.1204C>T) pathogenic?

SETD2 p.Arg402Trp (c.1204C>T) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-02). AlphaMissense: ambiguous (0.3465); Ultra-rare (popmax 0.019%, sas); Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Arg402Trp (c.1204C>T)?

SETD2 p.Arg402Trp (c.1204C>T) is associated with Inborn genetic diseases, Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg402Trp (c.1204C>T) in the general population?

SETD2 p.Arg402Trp (c.1204C>T) is ultra-rare (popmax 0.019%, sas) (gnomAD).

What do computational predictors say about SETD2 p.Arg402Trp (c.1204C>T)?

AlphaMissense predicts ambiguous (score 0.3465) — an in-silico prediction, not a clinical call.

SETD2 p.Arg402Trp

c.1204C>T · rs779483918 · VCV872545

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3465 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3465	ambiguous
REVEL	0.183	benign-leaning
SaProt	LLR -10.41	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 7.3	GERP 0.66, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	25.2	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 0.019% South Asian · 16/84,052 alleles

Filtering AF 0.0119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00968%

Overall 0.00238% 37/1,551,378 alleles · ultra-rare exomes 34/1,399,258 · genomes 3/152,120 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.019%	5,253
Remaining individualsnot grpmax-eligible	0.00499%	20,029
Admixed American	0.00196%	50,948
European (non-Finnish)	0.00139%	71,686
African / African-American	0.00137%	73,012

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.Arg402Trp
Coding: c.1204C>T
MANE Select: NM_014159
dbSNP: rs779483918
Type: single nucleotide variant
Location: chr3:47123432 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 402: 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

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

Also linked: Luscan-Lumish syndrome

Similar variants

SETD2 p.Arg402Gln Benign/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 c.4715+5G>A Uncertain significance ★★ same condition
SETD2 p.Ala1121Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Ala679Val Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg1065Cys 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-arg402trp (accessed [today's date]).

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