Is SETD2 p.Asp699Gly (c.2096A>G) pathogenic?

SETD2 p.Asp699Gly (c.2096A>G) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.0966); Rare (popmax 0.176%, sas); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Asp699Gly (c.2096A>G)?

SETD2 p.Asp699Gly (c.2096A>G) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Asp699Gly (c.2096A>G) in the general population?

SETD2 p.Asp699Gly (c.2096A>G) is rare (popmax 0.176%, sas) (gnomAD).

What do computational predictors say about SETD2 p.Asp699Gly (c.2096A>G)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

SETD2 p.Asp699Gly

c.2096A>G · rs368132877 · VCV1129449

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.176%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.395	indeterminate
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	23.2	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 0.176% South Asian · 160/91,082 alleles

Filtering AF 0.153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.0138% 222/1,614,118 alleles · rare exomes 213/1,461,782 · genomes 9/152,336 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.176%	569
Middle Eastern	0.132%	758
Remaining individualsnot grpmax-eligible	0.016%	6,251
European (non-Finnish)	0.00364%	27,441
African / African-American	0.00133%	75,052

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.Asp699Gly
Coding: c.2096A>G
MANE Select: NM_014159
dbSNP: rs368132877
Type: single nucleotide variant
Location: chr3:47122540 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 699: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation)

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.Asp699Val 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-asp699gly (accessed [today's date]).

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