Is SETD2 p.His2514= (c.7542C>T) pathogenic?

SETD2 p.His2514= (c.7542C>T) is classified Likely benign in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). Very rare (popmax 0.00167%, amr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.His2514= (c.7542C>T)?

SETD2 p.His2514= (c.7542C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.His2514= (c.7542C>T) in the general population?

SETD2 p.His2514= (c.7542C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

SETD2 p.His2514=

c.7542C>T · VCV3622269

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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	all four deltas below 0.2 · G>C here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.8	GERP -3.3
Overall
CADD	0.418	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,994 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00118% 19/1,613,850 alleles · very rare exomes 17/1,461,814 · genomes 2/152,036 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,994
European (non-Finnish)	0.00136%	73,751
African / African-American	0.00134%	74,840
South Asian	0.0011%	91,074

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.His2514=
Coding: c.7542C>T
MANE Select: NM_014159
Type: single nucleotide variant
Location: chr3:47017246 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 2514: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'interaction with polr2a' region; 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-his2514 (accessed [today's date]).

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