Is SETD2 p.Arg401Gln (c.1202G>A) pathogenic?

SETD2 p.Arg401Gln (c.1202G>A) is classified Uncertain significance in SETD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-21). AlphaMissense: likely benign (0.2168); Very rare (popmax 0.00476%, sas); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg401Gln (c.1202G>A)?

SETD2 p.Arg401Gln (c.1202G>A) is associated with Luscan-Lumish syndrome, Rabin-Pappas syndrome, intellectual developmental disorder, autosomal dominant 70 (ClinVar).

How common is SETD2 p.Arg401Gln (c.1202G>A) in the general population?

SETD2 p.Arg401Gln (c.1202G>A) is very rare (popmax 0.00476%, sas) (gnomAD).

What do computational predictors say about SETD2 p.Arg401Gln (c.1202G>A)?

AlphaMissense predicts likely benign (score 0.2168) — an in-silico prediction, not a clinical call.

SETD2 p.Arg401Gln

c.1202G>A · rs374918549 · VCV1057214

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00476%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.2168	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP 0.57, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	22.4	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 0.00476% South Asian · 4/84,048 alleles

Filtering AF 0.00254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00224%

Overall 0.00354% 55/1,551,566 alleles · very rare exomes 46/1,399,296 · genomes 9/152,270 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0116%	8,587
South Asiangrpmax	0.00476%	21,012
African / African-American	0.0041%	24,386
Admixed American	0.00392%	25,486
European (non-Finnish)	0.0034%	29,409

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg401Gln
Coding: c.1202G>A
MANE Select: NM_014159
dbSNP: rs374918549
Type: single nucleotide variant
Location: chr3:47123434 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 401: 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

Also linked: Rabin-Pappas syndrome intellectual developmental disorder, autosomal dominant 70

Similar variants

SETD2 p.Arg401Trp Uncertain significance ★ ⚠ same residue
SETD2 p.Arg401Leu 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-arg401gln (accessed [today's date]).

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