Is SETD2 p.Arg541Pro (c.1622G>C) pathogenic?

SETD2 p.Arg541Pro (c.1622G>C) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-30). AlphaMissense: ambiguous (0.4944); Very rare (popmax 8.48e-05%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg541Pro (c.1622G>C)?

SETD2 p.Arg541Pro (c.1622G>C) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg541Pro (c.1622G>C) in the general population?

SETD2 p.Arg541Pro (c.1622G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Arg541Pro (c.1622G>C)?

AlphaMissense predicts ambiguous (score 0.4944) — an in-silico prediction, not a clinical call.

SETD2 p.Arg541Pro

c.1622G>C · rs144677816 · VCV796585

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.4944	ambiguous
REVEL	0.233	benign-leaning
SaProt	LLR -7.12	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
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	24.6	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 8.48e-05% European (non-Finnish) · 1/1,179,880 alleles

Overall 6.2e-05% 1/1,614,002 alleles · very rare exomes 1/1,461,688 · genomes 0/152,314 · 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.Arg541Pro
Coding: c.1622G>C
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.Arg541Gln Benign ★ 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-arg541pro (accessed [today's date]).

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