Is SETD2 p.Arg1790Pro (c.5369G>C) pathogenic?

SETD2 p.Arg1790Pro (c.5369G>C) is classified Likely benign in SETD2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-31). AlphaMissense: likely pathogenic (0.5725); Very rare (popmax 0.0022%, sas); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg1790Pro (c.5369G>C)?

SETD2 p.Arg1790Pro (c.5369G>C) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg1790Pro (c.5369G>C) in the general population?

SETD2 p.Arg1790Pro (c.5369G>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about SETD2 p.Arg1790Pro (c.5369G>C)?

AlphaMissense predicts likely pathogenic (score 0.5725) — an in-silico prediction, not a clinical call.

SETD2 p.Arg1790Pro

c.5369G>C · rs376246790 · VCV135200

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.5725	likely pathogenic
REVEL	0.563	indeterminate
SaProt	LLR -5.83	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 14 kb · p 1.7e-10 · regional, not allelic
Overall
CADD	22.9	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 0.0022% South Asian · 2/91,046 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,066 alleles · very rare exomes 2/1,460,816 · genomes 0/152,250 · 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.Arg1790Pro
Coding: c.5369G>C
MANE Select: NM_014159
dbSNP: rs376246790
Type: single nucleotide variant
Location: chr3:47086223 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1790: 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

Disease context

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

Similar variants

SETD2 p.Arg1790Gln 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-arg1790pro (accessed [today's date]).

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