Is SETD2 p.Arg493Trp (c.1477C>T) pathogenic?

SETD2 p.Arg493Trp (c.1477C>T) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-09-14). AlphaMissense: likely benign (0.3143); Ultra-rare (popmax 0.0375%, sas); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg493Trp (c.1477C>T)?

SETD2 p.Arg493Trp (c.1477C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg493Trp (c.1477C>T) in the general population?

SETD2 p.Arg493Trp (c.1477C>T) is ultra-rare (popmax 0.0375%, sas) (gnomAD).

What do computational predictors say about SETD2 p.Arg493Trp (c.1477C>T)?

AlphaMissense predicts likely benign (score 0.3143) — an in-silico prediction, not a clinical call.

SETD2 p.Arg493Trp

c.1477C>T · rs778693117 · VCV542225

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3143 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0375%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.3143	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.9	GERP -1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	23.1	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0375% South Asian · 34/90,782 alleles

Filtering AF 0.0275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0241%

Overall 0.00522% 84/1,610,584 alleles · ultra-rare exomes 77/1,458,488 · genomes 7/152,096 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0375%	2,670
Remaining individualsnot grpmax-eligible	0.0112%	8,906
East Asian	0.00669%	14,939
African / African-American	0.00401%	24,941
Finnishnot grpmax-eligible	0.00313%	31,913
European (non-Finnish)	0.00297%	33,657

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.Arg493Trp
Coding: c.1477C>T
MANE Select: NM_014159
dbSNP: rs778693117
Type: single nucleotide variant
Location: chr3:47123159 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 493: 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.Arg493Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SETD2 p.Arg493Gly Uncertain significance ★ ⚠ 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

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-arg493trp (accessed [today's date]).

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