Is SETD2 p.Arg1708Pro (c.5123G>C) pathogenic?

SETD2 p.Arg1708Pro (c.5123G>C) is classified Likely pathogenic in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9623); Absent from gnomAD v4.1; Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg1708Pro (c.5123G>C)?

SETD2 p.Arg1708Pro (c.5123G>C) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg1708Pro (c.5123G>C) in the general population?

SETD2 p.Arg1708Pro (c.5123G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD2 p.Arg1708Pro (c.5123G>C)?

AlphaMissense predicts likely pathogenic (score 0.9623) — an in-silico prediction, not a clinical call.

SETD2 p.Arg1708Pro

c.5123G>C · rs2107674146 · VCV3065245

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9623 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.9623	likely pathogenic ✓ concordant with ClinVar
REVEL	0.661	pathogenic-leaning
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 19 kb · p 4.3e-27 · regional, not allelic
Overall
CADD	27.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SETD2
Protein: p.Arg1708Pro
Coding: c.5123G>C
MANE Select: NM_014159
dbSNP: rs2107674146
Type: single nucleotide variant
Location: chr3:47097974 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1708: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'interaction with tuba1a' 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.Arg1708= Likely benign ★ same residue
SETD2 p.Arg1708Ter Likely pathogenic ★ 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-arg1708pro (accessed [today's date]).

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