Is SETD2 p.Arg2490Trp (c.7468C>T) pathogenic?

SETD2 p.Arg2490Trp (c.7468C>T) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-05). AlphaMissense: likely pathogenic (0.9965); Very rare (popmax 0.00446%, eas); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg2490Trp (c.7468C>T)?

SETD2 p.Arg2490Trp (c.7468C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg2490Trp (c.7468C>T) in the general population?

SETD2 p.Arg2490Trp (c.7468C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about SETD2 p.Arg2490Trp (c.7468C>T)?

AlphaMissense predicts likely pathogenic (score 0.9965) — an in-silico prediction, not a clinical call.

SETD2 p.Arg2490Trp

c.7468C>T · rs772135964 · VCV1490895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.9965	likely pathogenic · top 4% in SETD2
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -10.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 20 kb · p 1.6e-07 · regional, not allelic
Overall
CADD	24.1	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,890 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,613,960 alleles · very rare exomes 5/1,461,706 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,445
Admixed American	0.00167%	60,018
African / African-American	0.00133%	74,990
South Asian	0.0011%	91,082

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.Arg2490Trp
Coding: c.7468C>T
MANE Select: NM_014159
dbSNP: rs772135964
Type: single nucleotide variant
Location: chr3:47017703 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 2490: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'interaction with polr2a' 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.Arg2490Leu 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
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-arg2490trp (accessed [today's date]).

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