Is SET p.Leu95Pro (c.284T>C) pathogenic?

SET p.Leu95Pro (c.284T>C) is classified Uncertain significance in SET (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SET p.Leu95Pro (c.284T>C)?

SET p.Leu95Pro (c.284T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SET p.Leu95Pro (c.284T>C) in the general population?

SET p.Leu95Pro (c.284T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SET p.Leu95Pro (c.284T>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

SET p.Leu95Pro

c.284T>C · rs2490436602 · VCV2623038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic · top 6% in SET
REVEL	0.509	indeterminate
SaProt	LLR -16.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 4,260 bp · p 5.8e-31 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L108P vs ClinVar L95P) — verify the residue.

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: SET
Protein: p.Leu95Pro
Coding: c.284T>C
MANE Select: NM_003011
dbSNP: rs2490436602
Type: single nucleotide variant
Location: chr9:128692671 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.62 · 3 PDB
Residue 95: a UniProt-annotated variant site (in mrd58); an α-helix; the 'earmuff domain' region

Full SET 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

SET p.Asp260Glu Uncertain significance ★★ ⚠ same condition
SET p.Glu261Asp Uncertain significance ★★ ⚠ same condition
SET p.Asp235Glu Likely benign ★★ same condition
SET c.492+4T>C Uncertain significance ★ same condition
SET p.Glu233Gly Uncertain significance ★ ⚠ same condition
SET p.Glu271Asp Uncertain significance ★ ⚠ same condition
SET p.Thr167Met Uncertain significance ★ ⚠ same condition
SET p.Thr173Met Likely benign ★ 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/set-p-leu95pro (accessed [today's date]).

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