Is SETD2 p.Thr928Arg (c.2783C>G) pathogenic?

SETD2 p.Thr928Arg (c.2783C>G) is classified Benign/Likely benign in SETD2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.085); Rare (popmax 0.814%, afr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Thr928Arg (c.2783C>G)?

SETD2 p.Thr928Arg (c.2783C>G) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Thr928Arg (c.2783C>G) in the general population?

SETD2 p.Thr928Arg (c.2783C>G) is rare (popmax 0.814%, afr) (gnomAD).

What do computational predictors say about SETD2 p.Thr928Arg (c.2783C>G)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

SETD2 p.Thr928Arg

c.2783C>G · rs72895708 · VCV135222

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.814%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.23, phastCons 0.79
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	14.27	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 0.814% African / African-American · 610/74,968 alleles

Filtering AF 0.76% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.739%

Overall 0.0506% 816/1,613,894 alleles · rare exomes 486/1,461,772 · genomes 330/152,122 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.814%	123
Middle Eastern	0.165%	606
Admixed American	0.112%	896
Remaining individualsnot grpmax-eligible	0.072%	1,389
European (non-Finnish)	0.00703%	14,217
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590

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.Thr928Arg
Coding: c.2783C>G
MANE Select: NM_014159
dbSNP: rs72895708
Type: single nucleotide variant
Location: chr3:47121853 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 928: 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.Thr928Ile 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-thr928arg (accessed [today's date]).

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