Is SETD2 p.Arg2040Ter (c.6118C>T) pathogenic?

SETD2 p.Arg2040Ter (c.6118C>T) is classified Likely pathogenic in SETD2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-11-04). No allele count reported in gnomAD v4.1 (AN 1,587,910); Associated with SETD2-related disorder.

What condition is associated with SETD2 p.Arg2040Ter (c.6118C>T)?

SETD2 p.Arg2040Ter (c.6118C>T) is associated with SETD2-related disorder (ClinVar).

How common is SETD2 p.Arg2040Ter (c.6118C>T) in the general population?

SETD2 p.Arg2040Ter (c.6118C>T) is no allele count reported in gnomAD v4.1 (AN 1,587,910) (gnomAD).

SETD2 p.Arg2040Ter

c.6118C>T · VCV4530259

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,587,910)

Conditions

SETD2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 14 of 21
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.7, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,587,910). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SETD2
Protein: p.Arg2040Ter
Coding: c.6118C>T
MANE Select: NM_014159
Type: single nucleotide variant
Location: chr3:47062338 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 2040: 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

SETD2-related disorder

Similar variants

SETD2 p.Arg2040Gly Uncertain significance ★ same residue
SETD2 p.Arg2040Pro Uncertain significance ★ ⚠ same residue
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same condition
SETD2 p.Glu1430Gly Uncertain significance ★★ ⚠ same condition
SETD2 p.Ser1056Leu Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg620Ter Likely pathogenic ★ same condition
SETD2 p.Gln2342Ter Likely pathogenic ★ same condition
SETD2 p.Trp1827Ter Likely pathogenic ★ 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-arg2040ter (accessed [today's date]).

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