Is SETD2 p.Ala2357= (c.7071A>G) pathogenic?

SETD2 p.Ala2357= (c.7071A>G) is classified Likely benign in SETD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-27). Ultra-rare (popmax 0.0495%, afr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Ala2357= (c.7071A>G)?

SETD2 p.Ala2357= (c.7071A>G) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ala2357= (c.7071A>G) in the general population?

SETD2 p.Ala2357= (c.7071A>G) is ultra-rare (popmax 0.0495%, afr) (gnomAD).

SETD2 p.Ala2357=

c.7071A>G · rs140288461 · VCV767107

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, 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 -3.4	GERP -3.2
Overall
CADD	2.515	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% African / African-American · 37/74,812 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00255% 41/1,608,510 alleles · ultra-rare exomes 16/1,456,330 · genomes 25/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0495%	2,022
Remaining individualsnot grpmax-eligible	0.00483%	20,706
Admixed American	0.00169%	59,324

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.Ala2357=
Coding: c.7071A>G
MANE Select: NM_014159
dbSNP: rs140288461
Type: single nucleotide variant
Location: chr3:47046514 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 2357: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'low charge region' 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.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-ala2357 (accessed [today's date]).

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