Is SETD2 p.Pro668His (c.2003C>A) pathogenic?

SETD2 p.Pro668His (c.2003C>A) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-25). AlphaMissense: likely benign (0.1086); Very rare (popmax 0.005%, amr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Pro668His (c.2003C>A)?

SETD2 p.Pro668His (c.2003C>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Pro668His (c.2003C>A) in the general population?

SETD2 p.Pro668His (c.2003C>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about SETD2 p.Pro668His (c.2003C>A)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

SETD2 p.Pro668His

c.2003C>A · rs1019436227 · VCV1001847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.375	indeterminate
SaProt	LLR -6.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,982 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000372% 6/1,613,430 alleles · very rare exomes 4/1,461,374 · genomes 2/152,056 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,994
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.00017%	589,835

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.Pro668His
Coding: c.2003C>A
MANE Select: NM_014159
dbSNP: rs1019436227
Type: single nucleotide variant
Location: chr3:47122633 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 668: 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

Luscan-Lumish syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD2 p.Pro668Ala 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 p.Ala1121Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Ala679Val Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg1065Cys Uncertain significance ★★ same condition
SETD2 p.Arg329Gln 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-pro668his (accessed [today's date]).

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