Is SETD2 p.Cys531del (c.1589GTT[1]) pathogenic?

SETD2 p.Cys531del (c.1589GTT[1]) is classified Likely benign in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-30). Very rare (popmax 0.00636%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Cys531del (c.1589GTT[1])?

SETD2 p.Cys531del (c.1589GTT[1]) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Cys531del (c.1589GTT[1]) in the general population?

SETD2 p.Cys531del (c.1589GTT[1]) is very rare (popmax 0.00636%, nfe) (gnomAD).

SETD2 p.Cys531del

c.1589GTT[1] · rs773040363 · VCV833853

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

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 · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 2.5, phastCons 1
Overall
CADD	13.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00636% European (non-Finnish) · 75/1,179,972 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00477% 77/1,613,958 alleles · very rare exomes 75/1,461,746 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00636%	15,733
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Cys531del
Coding: c.1589GTT[1]
MANE Select: NM_014159
dbSNP: rs773040363
Type: Microsatellite
Location: chr3:47123042 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 531: a UniProt-annotated variant site (in aml; 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.Asp429_Ser430insTer Pathogenic/Likely pathogenic ★★ same condition
SETD2 p.Asp1841fs Likely pathogenic ★ same condition
SETD2 p.Leu1729_Ser1730insTer Pathogenic ★ same condition
SETD2 p.Val2282fs Pathogenic ★ same condition
SETD2 c.4917+3_4917+6del Uncertain significance ★ same condition
SETD2 p.Pro194_Pro196dup Uncertain significance ★ same condition
SETD2 p.Val930del Uncertain significance ★ same condition
SETD2 c.7099-19GT[3] Likely benign ★ 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-cys531del (accessed [today's date]).

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