Is SETD2 p.Ile563Val (c.1687A>G) pathogenic?

SETD2 p.Ile563Val (c.1687A>G) is classified Benign/Likely benign in SETD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-11-06). AlphaMissense: likely benign (0.0591); Very rare (popmax 0.00835%, amr); Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Ile563Val (c.1687A>G)?

SETD2 p.Ile563Val (c.1687A>G) is associated with Inborn genetic diseases, Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ile563Val (c.1687A>G) in the general population?

SETD2 p.Ile563Val (c.1687A>G) is very rare (popmax 0.00835%, amr) (gnomAD).

What do computational predictors say about SETD2 p.Ile563Val (c.1687A>G)?

AlphaMissense predicts likely benign (score 0.0591) — an in-silico prediction, not a clinical call.

SETD2 p.Ile563Val

c.1687A>G · rs587778668 · VCV135210

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00835%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0591	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -5.47	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 -0.93	GERP -4.7
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	2.148	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 0.00835% Admixed American · 5/59,846 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000496% 8/1,613,326 alleles · very rare exomes 6/1,461,082 · genomes 2/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00835%	11,969
Finnishnot grpmax-eligible	0.00156%	64,032
African / African-American	0.00134%	74,880
European (non-Finnish)	8.48e-05%	1,179,647

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.Ile563Val
Coding: c.1687A>G
MANE Select: NM_014159
dbSNP: rs587778668
Type: single nucleotide variant
Location: chr3:47122949 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 563: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Luscan-Lumish syndrome

Similar variants

SETD2 p.Ile563Thr Uncertain significance ★★ ⚠ same residue
SETD2 p.Arg1598Ter Pathogenic/Likely pathogenic ★★ same condition
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same condition
SETD2 p.Arg1740Trp Pathogenic/Likely pathogenic ★★ same condition
SETD2 c.4715+5G>A Uncertain significance ★★ same condition
SETD2 p.Ala1121Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Ala679Val Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg1065Cys 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-ile563val (accessed [today's date]).

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