Is SETD2 p.Arg541Gln (c.1622G>A) pathogenic?

SETD2 p.Arg541Gln (c.1622G>A) is classified Benign in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-25). AlphaMissense: likely benign (0.1437); Ultra-rare (popmax 0.0182%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg541Gln (c.1622G>A)?

SETD2 p.Arg541Gln (c.1622G>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg541Gln (c.1622G>A) in the general population?

SETD2 p.Arg541Gln (c.1622G>A) is ultra-rare (popmax 0.0182%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Arg541Gln (c.1622G>A)?

AlphaMissense predicts likely benign (score 0.1437) — an in-silico prediction, not a clinical call.

SETD2 p.Arg541Gln

c.1622G>A · rs144677816 · VCV1169273

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1437 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.1437	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -7.32	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 6	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	25.0	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 0.0182% European (non-Finnish) · 215/1,179,888 alleles

Filtering AF 0.0162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.0142% 229/1,613,882 alleles · ultra-rare exomes 221/1,461,686 · genomes 8/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0182%	5,488
East Asian	0.00891%	11,222
Remaining individualsnot grpmax-eligible	0.008%	12,496
Admixed American	0.00667%	14,999
South Asian	0.0011%	91,078

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.Arg541Gln
Coding: c.1622G>A
MANE Select: NM_014159
dbSNP: rs144677816
Type: single nucleotide variant
Location: chr3:47123014 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 541: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); the 'disordered' region

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.Arg541Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
SETD2 p.Arg541Leu 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

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-arg541gln (accessed [today's date]).

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