Is SETD2 p.Ser996= (c.2988A>G) pathogenic?

SETD2 p.Ser996= (c.2988A>G) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-16). Ultra-rare (popmax 0.0187%, afr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Ser996= (c.2988A>G)?

SETD2 p.Ser996= (c.2988A>G) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ser996= (c.2988A>G) in the general population?

SETD2 p.Ser996= (c.2988A>G) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

SETD2 p.Ser996=

c.2988A>G · rs772906890 · VCV475505

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, 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 -0.17	GERP -1.3, phastCons 0.7
Overall
CADD	5.702	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,944 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.0026% 42/1,614,018 alleles · ultra-rare exomes 39/1,461,792 · genomes 3/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,353
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00195%	51,304
Admixed American	0.00167%	60,000
Finnishnot grpmax-eligible	0.00156%	64,014
South Asian	0.0011%	91,086

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.Ser996=
Coding: c.2988A>G
MANE Select: NM_014159
dbSNP: rs772906890
Type: single nucleotide variant
Location: chr3:47121648 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 996: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; 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.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
SETD2 p.Arg368Gln 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-ser996 (accessed [today's date]).

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