Is SETD2 p.Arg1708Ter (c.5122C>T) pathogenic?

SETD2 p.Arg1708Ter (c.5122C>T) is classified Likely pathogenic in SETD2 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 8.48e-05%, nfe); Associated with autism spectrum disorder.

What condition is associated with SETD2 p.Arg1708Ter (c.5122C>T)?

SETD2 p.Arg1708Ter (c.5122C>T) is associated with autism spectrum disorder (ClinVar).

How common is SETD2 p.Arg1708Ter (c.5122C>T) in the general population?

SETD2 p.Arg1708Ter (c.5122C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

SETD2 p.Arg1708Ter

c.5122C>T · rs774671060 · VCV2429923

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

autism spectrum 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 9 of 21
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.5, phastCons 1
Overall
CADD	37.0	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,738 alleles

Overall 6.2e-05% 1/1,613,592 alleles · very rare exomes 0/1,461,452 · genomes 1/152,140 · 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.Arg1708Ter
Coding: c.5122C>T
MANE Select: NM_014159
dbSNP: rs774671060
Type: single nucleotide variant
Location: chr3:47097975 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1708: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'interaction with tuba1a' region

Full SETD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autism spectrum disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD2 p.Arg1708Pro Likely pathogenic ★ ⚠ same residue
SETD2 p.Arg1708= Likely benign ★ same residue
SETD2 p.Asn1488Lys Likely benign ★ ⚠ same condition
SETD2 p.Asp2004Gly Likely benign ★ same condition
SETD2 p.Gln2335Arg Likely benign ★ same condition
SETD2 p.Lys57Arg Likely benign ★ same condition
SETD2 p.Arg1598Ter Pathogenic/Likely pathogenic ★★ same type
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same type

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-arg1708ter (accessed [today's date]).

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