Is SETD2 p.Val2003= (c.6009G>A) pathogenic?

SETD2 p.Val2003= (c.6009G>A) is classified Benign in SETD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-11-02). Rare (popmax 0.139%, afr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Val2003= (c.6009G>A)?

SETD2 p.Val2003= (c.6009G>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Val2003= (c.6009G>A) in the general population?

SETD2 p.Val2003= (c.6009G>A) is rare (popmax 0.139%, afr) (gnomAD).

SETD2 p.Val2003=

c.6009G>A · rs148671940 · VCV542239

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.139%, afr)

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.1	phastCons 0.96
Overall
CADD	5.576	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.139% African / African-American · 104/75,006 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.109%

Overall 0.00694% 112/1,613,978 alleles · rare exomes 52/1,461,756 · genomes 60/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.139%	721
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.00333%	29,994
European (non-Finnish)	8.47e-05%	1,179,958

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.Val2003=
Coding: c.6009G>A
MANE Select: NM_014159
dbSNP: rs148671940
Type: single nucleotide variant
Location: chr3:47083771 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 2003: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; 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.Val2003Met 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-val2003 (accessed [today's date]).

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