Is SETD2 p.Phe1454Leu (c.4362C>G) pathogenic?

SETD2 p.Phe1454Leu (c.4362C>G) is classified Likely benign in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-06). AlphaMissense: likely pathogenic (0.9957); Absent from gnomAD v4.1; Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Phe1454Leu (c.4362C>G)?

SETD2 p.Phe1454Leu (c.4362C>G) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Phe1454Leu (c.4362C>G) in the general population?

SETD2 p.Phe1454Leu (c.4362C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD2 p.Phe1454Leu (c.4362C>G)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

SETD2 p.Phe1454Leu

c.4362C>G · rs2107739769 · VCV2866222

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9957 · 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	0.9957	likely pathogenic · top 5% in SETD2
REVEL	0.712	pathogenic-leaning
SaProt	LLR -2.71	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -0.19, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 3,616 bp · p 0.0011 · regional, not allelic
Overall
CADD	20.2	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.Phe1454Leu
Coding: c.4362C>G
MANE Select: NM_014159
dbSNP: rs2107739769
Type: single nucleotide variant
Location: chr3:47120274 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1454: 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; an α-helix

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.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
SETD2 p.Arg329Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg368Gln 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-phe1454leu (accessed [today's date]).

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