Is SETD2 p.Ser1417Ile (c.4250G>T) pathogenic?

SETD2 p.Ser1417Ile (c.4250G>T) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-24). AlphaMissense: ambiguous (0.5203); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Ser1417Ile (c.4250G>T)?

SETD2 p.Ser1417Ile (c.4250G>T) is associated with Inborn genetic diseases, Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ser1417Ile (c.4250G>T) in the general population?

SETD2 p.Ser1417Ile (c.4250G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD2 p.Ser1417Ile (c.4250G>T)?

AlphaMissense predicts ambiguous (score 0.5203) — an in-silico prediction, not a clinical call.

SETD2 p.Ser1417Ile

c.4250G>T · rs762132169 · VCV833571

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5203 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5203	ambiguous
REVEL	0.566	indeterminate
SaProt	LLR -9.13	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	22.6	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

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.Ser1417Ile
Coding: c.4250G>T
MANE Select: NM_014159
dbSNP: rs762132169
Type: single nucleotide variant
Location: chr3:47120386 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1417: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'disordered' region; a modified residue (phosphoserine)

Full SETD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Luscan-Lumish syndrome

Similar variants

SETD2 p.Arg1598Ter Pathogenic/Likely pathogenic ★★ same condition
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same condition
SETD2 p.Arg1740Trp Pathogenic/Likely pathogenic ★★ same condition
SETD2 c.4715+5G>A Uncertain significance ★★ same condition
SETD2 p.Ala1121Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Ala679Val Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg1065Cys Uncertain significance ★★ same condition
SETD2 p.Arg1197Thr 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-ser1417ile (accessed [today's date]).

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