Is SETD2 p.Arg1065Cys (c.3193C>T) pathogenic?

SETD2 p.Arg1065Cys (c.3193C>T) is classified Uncertain significance in SETD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-18). AlphaMissense: ambiguous (0.5202); Ultra-rare (popmax 0.0111%, eas); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg1065Cys (c.3193C>T)?

SETD2 p.Arg1065Cys (c.3193C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg1065Cys (c.3193C>T) in the general population?

SETD2 p.Arg1065Cys (c.3193C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about SETD2 p.Arg1065Cys (c.3193C>T)?

AlphaMissense predicts ambiguous (score 0.5202) — an in-silico prediction, not a clinical call.

SETD2 p.Arg1065Cys

c.3193C>T · rs765867260 · VCV578109

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5202 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.5202	ambiguous
REVEL	0.479	indeterminate
SaProt	LLR -7.47	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,882 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000868% 14/1,612,328 alleles · ultra-rare exomes 11/1,460,246 · genomes 3/152,082 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,976
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.000678%	147,498

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.Arg1065Cys
Coding: c.3193C>T
MANE Select: NM_014159
dbSNP: rs765867260
Type: single nucleotide variant
Location: chr3:47121443 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1065: the 'disordered' region; a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation)

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.Arg329Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg368Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg401Gln 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-arg1065cys (accessed [today's date]).

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