Is SETD2 p.Thr1848= (c.5544A>G) pathogenic?

SETD2 p.Thr1848= (c.5544A>G) is classified Likely benign in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-30). Very rare (popmax 0.00334%, amr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Thr1848= (c.5544A>G)?

SETD2 p.Thr1848= (c.5544A>G) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Thr1848= (c.5544A>G) in the general population?

SETD2 p.Thr1848= (c.5544A>G) is very rare (popmax 0.00334%, amr) (gnomAD).

SETD2 p.Thr1848=

c.5544A>G · rs770995434 · VCV757894

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00334%, 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 -3.3
Overall
CADD	4.595	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,968 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000682% 11/1,614,008 alleles · very rare exomes 10/1,461,840 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,984
African / African-American	0.00133%	74,916
European (non-Finnish)	0.000678%	147,502

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.Thr1848=
Coding: c.5544A>G
MANE Select: NM_014159
dbSNP: rs770995434
Type: single nucleotide variant
Location: chr3:47084236 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1848: 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.Thr1848Ala 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-thr1848 (accessed [today's date]).

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