Is SETD2 p.Gln1981Arg (c.5942A>G) pathogenic?

SETD2 p.Gln1981Arg (c.5942A>G) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-27). AlphaMissense: likely pathogenic (0.6446); Ultra-rare (popmax 0.0133%, amr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Gln1981Arg (c.5942A>G)?

SETD2 p.Gln1981Arg (c.5942A>G) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Gln1981Arg (c.5942A>G) in the general population?

SETD2 p.Gln1981Arg (c.5942A>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about SETD2 p.Gln1981Arg (c.5942A>G)?

AlphaMissense predicts likely pathogenic (score 0.6446) — an in-silico prediction, not a clinical call.

SETD2 p.Gln1981Arg

c.5942A>G · rs189529024 · VCV542223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6446 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.6446	likely pathogenic
REVEL	0.196	benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 556 bp · p 0.19 · regional, not allelic
Overall
CADD	24.4	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 0.0133% Admixed American · 8/60,022 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000496% 8/1,614,110 alleles · ultra-rare exomes 6/1,461,806 · genomes 2/152,304 · joint denominator

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.Gln1981Arg
Coding: c.5942A>G
MANE Select: NM_014159
dbSNP: rs189529024
Type: single nucleotide variant
Location: chr3:47083838 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1981: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; 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.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-gln1981arg (accessed [today's date]).

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