Is SETD2 p.Leu55Phe (c.165G>T) pathogenic?

SETD2 p.Leu55Phe (c.165G>T) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-15). AlphaMissense: likely pathogenic (0.8665); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Leu55Phe (c.165G>T)?

SETD2 p.Leu55Phe (c.165G>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD2 p.Leu55Phe (c.165G>T) in the general population?

SETD2 p.Leu55Phe (c.165G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD2 p.Leu55Phe (c.165G>T)?

AlphaMissense predicts likely pathogenic (score 0.8665) — an in-silico prediction, not a clinical call.

SETD2 p.Leu55Phe

c.165G>T · rs2545655870 · VCV2287207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8665 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8665	likely pathogenic
REVEL	0.536	indeterminate
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 40 kb · p 0.036 · regional, not allelic
Overall
CADD	22.1	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.Leu55Phe
Coding: c.165G>T
MANE Select: NM_014159
dbSNP: rs2545655870
Type: single nucleotide variant
Location: chr3:47124471 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB

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

Similar variants

SETD2 c.4715+5G>A Uncertain significance ★★ same condition
SETD2 p.Arg1197Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg368Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg540Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Asn1303Ser Uncertain significance ★★ ⚠ same condition
SETD2 p.Asn840Ser Uncertain significance ★★ ⚠ same condition
SETD2 p.Asp1169Gly Uncertain significance ★★ ⚠ same condition
SETD2 p.Asp294Val 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-leu55phe (accessed [today's date]).

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