Is SETD2 p.Thr2388= (c.7164C>T) pathogenic?

SETD2 p.Thr2388= (c.7164C>T) is classified Benign/Likely benign in SETD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-01). Ultra-rare (popmax 0.096%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Thr2388= (c.7164C>T)?

SETD2 p.Thr2388= (c.7164C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Thr2388= (c.7164C>T) in the general population?

SETD2 p.Thr2388= (c.7164C>T) is ultra-rare (popmax 0.096%, nfe) (gnomAD).

SETD2 p.Thr2388=

c.7164C>T · rs144752494 · VCV475538

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.096%, nfe)

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.69	GERP -2.8
Overall
CADD	3.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.096% European (non-Finnish) · 1,132/1,179,748 alleles

Filtering AF 0.0912% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0894%

Overall 0.0731% 1,179/1,613,428 alleles · ultra-rare exomes 1,112/1,461,228 · genomes 67/152,200 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.096%	1,042
Remaining individualsnot grpmax-eligible	0.0368%	2,716
African / African-American	0.0253%	3,946
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,576
Admixed American	0.00334%	29,932
Finnishnot grpmax-eligible	0.00313%	31,998

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.Thr2388=
Coding: c.7164C>T
MANE Select: NM_014159
dbSNP: rs144752494
Type: single nucleotide variant
Location: chr3:47042635 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 2388: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); an α-helix

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-thr2388 (accessed [today's date]).

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