Is SETD2 p.Ser1056= (c.3168G>A) pathogenic?

SETD2 p.Ser1056= (c.3168G>A) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-04). Ultra-rare (popmax 0.0117%, amr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Ser1056= (c.3168G>A)?

SETD2 p.Ser1056= (c.3168G>A) is associated with Luscan-Lumish syndrome, Rabin-Pappas syndrome, intellectual developmental disorder, autosomal dominant 70 (ClinVar).

How common is SETD2 p.Ser1056= (c.3168G>A) in the general population?

SETD2 p.Ser1056= (c.3168G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

SETD2 p.Ser1056=

c.3168G>A · rs768944836 · VCV1337950

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

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 2.1	GERP -1.8, phastCons 1
Overall
CADD	8.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,004 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000496% 8/1,613,544 alleles · ultra-rare exomes 8/1,461,316 · genomes 0/152,228 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,572
South Asian	0.0011%	91,076

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.Ser1056=
Coding: c.3168G>A
MANE Select: NM_014159
dbSNP: rs768944836
Type: single nucleotide variant
Location: chr3:47121468 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1056: the 'disordered' region; 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

Also linked: Rabin-Pappas syndrome intellectual developmental disorder, autosomal dominant 70

Similar variants

SETD2 p.Ser1056Leu 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-ser1056 (accessed [today's date]).

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