Is SETD2 p.Arg329Trp (c.985C>T) pathogenic?

SETD2 p.Arg329Trp (c.985C>T) is classified Benign/Likely benign in SETD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-04). AlphaMissense: likely benign (0.1283); Ultra-rare (popmax 0.0124%, afr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg329Trp (c.985C>T)?

SETD2 p.Arg329Trp (c.985C>T) is associated with Luscan-Lumish syndrome, hereditary ataxia (ClinVar).

How common is SETD2 p.Arg329Trp (c.985C>T) in the general population?

SETD2 p.Arg329Trp (c.985C>T) is ultra-rare (popmax 0.0124%, afr) (gnomAD).

What do computational predictors say about SETD2 p.Arg329Trp (c.985C>T)?

AlphaMissense predicts likely benign (score 0.1283) — an in-silico prediction, not a clinical call.

SETD2 p.Arg329Trp

c.985C>T · rs372869995 · VCV848909

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1283 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.1283	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -8.74	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 5.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 165 bp · p 0.0033 · regional, not allelic
Overall
CADD	23.6	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 0.0124% African / African-American · 9/72,868 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00479%

Overall 0.00516% 80/1,550,316 alleles · ultra-rare exomes 69/1,398,174 · genomes 11/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0124%	8,096
Remaining individualsnot grpmax-eligible	0.00833%	12,006
Admixed American	0.0079%	12,658
European (non-Finnish)	0.00532%	18,799
East Asian	0.00244%	40,908

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.Arg329Trp
Coding: c.985C>T
MANE Select: NM_014159
dbSNP: rs372869995
Type: single nucleotide variant
Location: chr3:47123651 (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

Also linked: hereditary ataxia

Similar variants

SETD2 p.Arg329Gln Uncertain significance ★★ ⚠ same residue
SETD2 p.Arg329= 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-arg329trp (accessed [today's date]).

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