Is SETD2 p.Arg1826Cys (c.5476C>T) pathogenic?

SETD2 p.Arg1826Cys (c.5476C>T) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-23). AlphaMissense: ambiguous (0.4932); Very rare (popmax 0.00133%, afr).

How common is SETD2 p.Arg1826Cys (c.5476C>T) in the general population?

SETD2 p.Arg1826Cys (c.5476C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SETD2 p.Arg1826Cys (c.5476C>T)?

AlphaMissense predicts ambiguous (score 0.4932) — an in-silico prediction, not a clinical call.

SETD2 p.Arg1826Cys

c.5476C>T · VCV4962259

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
AlphaMissense	0.4932	ambiguous
REVEL	0.389	indeterminate
SaProt	LLR -8.46	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 556 bp · p 0.19 · regional, not allelic
Overall
CADD	29.3	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 0.00133% African / African-American · 1/74,976 alleles

Overall 6.2e-05% 1/1,613,796 alleles · very rare exomes 1/1,461,692 · genomes 0/152,104 · 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.Arg1826Cys
Coding: c.5476C>T
MANE Select: NM_014159
Type: single nucleotide variant
Location: chr3:47084304 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1826: 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

Similar variants

SETD2 p.Arg1826= Likely benign ★ same residue
SETD2 p.Arg1598Ter Pathogenic/Likely pathogenic ★★ same type
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same type
SETD2 p.Arg1740Trp Pathogenic/Likely pathogenic ★★ same type
SETD2 p.Arg441Ter Likely pathogenic ★★ same type
SETD2 p.Glu1718Lys Likely pathogenic ★★ ⚠ same type
SETD2 c.4715+5G>A Uncertain significance ★★ same type
SETD2 p.Ala1121Thr Uncertain significance ★★ ⚠ 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-arg1826cys (accessed [today's date]).

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