Is SETD2 p.Arg329Gln (c.986G>A) pathogenic?

SETD2 p.Arg329Gln (c.986G>A) is classified Uncertain significance in SETD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-24). AlphaMissense: likely benign (0.0683); Very rare (popmax 0.00594%, amr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg329Gln (c.986G>A)?

SETD2 p.Arg329Gln (c.986G>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg329Gln (c.986G>A) in the general population?

SETD2 p.Arg329Gln (c.986G>A) is very rare (popmax 0.00594%, amr) (gnomAD).

What do computational predictors say about SETD2 p.Arg329Gln (c.986G>A)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

SETD2 p.Arg329Gln

c.986G>A · rs540015912 · VCV805408

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00594%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -7.31	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 2.7	GERP 0.57, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 165 bp · p 0.0033 · regional, not allelic
Overall
CADD	20.2	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 0.00594% Admixed American · 3/50,524 alleles

Filtering AF 0.00335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00303%

Overall 0.00374% 58/1,550,066 alleles · very rare exomes 50/1,397,786 · genomes 8/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00594%	16,841
European (non-Finnish)	0.00436%	22,933
African / African-American	0.00411%	24,321
East Asian	0.00244%	40,900
Remaining individualsnot grpmax-eligible	0.00167%	60,010

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.Arg329Gln
Coding: c.986G>A
MANE Select: NM_014159
dbSNP: rs540015912
Type: single nucleotide variant
Location: chr3:47123650 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 329: 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.Arg329= Benign/Likely benign ★★ same residue
SETD2 p.Arg329Trp Benign/Likely benign ★★ 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-arg329gln (accessed [today's date]).

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