Is SETD2 p.His2249Arg (c.6746A>G) pathogenic?

SETD2 p.His2249Arg (c.6746A>G) is classified Likely benign in SETD2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-01). AlphaMissense: likely benign (0.1737); Ultra-rare (popmax 0.0557%, eas); Associated with SETD2-related disorder.

What condition is associated with SETD2 p.His2249Arg (c.6746A>G)?

SETD2 p.His2249Arg (c.6746A>G) is associated with SETD2-related disorder (ClinVar).

How common is SETD2 p.His2249Arg (c.6746A>G) in the general population?

SETD2 p.His2249Arg (c.6746A>G) is ultra-rare (popmax 0.0557%, eas) (gnomAD).

What do computational predictors say about SETD2 p.His2249Arg (c.6746A>G)?

AlphaMissense predicts likely benign (score 0.1737) — an in-silico prediction, not a clinical call.

SETD2 p.His2249Arg

c.6746A>G · rs756854758 · VCV3057563

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0557%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SETD2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1737	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -6.66	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 5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 19 kb · p 0.00059 · regional, not allelic
Overall
CADD	21.0	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 0.0557% East Asian · 25/44,894 alleles

Filtering AF 0.0387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00161% 26/1,614,106 alleles · ultra-rare exomes 23/1,461,890 · genomes 3/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0557%	1,796
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.His2249Arg
Coding: c.6746A>G
MANE Select: NM_014159
dbSNP: rs756854758
Type: single nucleotide variant
Location: chr3:47057038 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 2249: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'low charge region' region

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

Disease context

SETD2-related disorder

Similar variants

SETD2 p.His2249= Likely benign ★ same residue
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same condition
SETD2 p.Glu1430Gly Uncertain significance ★★ ⚠ same condition
SETD2 p.Ser1056Leu Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg2040Ter Likely pathogenic ★ 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-his2249arg (accessed [today's date]).

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