Is SET p.Pro90Ser (c.268C>T) pathogenic?

SET p.Pro90Ser (c.268C>T) is classified Uncertain significance in SET (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). AlphaMissense: likely pathogenic (0.9965); Absent from gnomAD v4.1.

How common is SET p.Pro90Ser (c.268C>T) in the general population?

SET p.Pro90Ser (c.268C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SET p.Pro90Ser (c.268C>T)?

AlphaMissense predicts likely pathogenic (score 0.9965) — an in-silico prediction, not a clinical call.

SET p.Pro90Ser

c.268C>T · rs2132251340 · VCV1304282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9965 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9965	likely pathogenic
REVEL	0.26	benign-leaning
SaProt	LLR -15.44	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 4,260 bp · p 5.8e-31 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P103S vs ClinVar P90S) — 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.Pro90Ser
Coding: c.268C>T
MANE Select: NM_003011
dbSNP: rs2132251340
Type: single nucleotide variant
Location: chr9:128691994 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.62 · 3 PDB
Residue 103 UniProt numbering: a turn; the 'earmuff domain' region

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

Similar variants

SET p.Pro90Gln Uncertain significance ★ ⚠ same residue
SET c.663+5G>C Pathogenic ★★ same type
SET p.His105Tyr Likely pathogenic ★★ same type
SET p.Asp224Asn Uncertain significance ★★ ⚠ same type
SET p.Asp260Glu Uncertain significance ★★ ⚠ same type
SET p.Glu261Asp Uncertain significance ★★ ⚠ same type
SET p.Phe189Cys Uncertain significance ★★ ⚠ same type
SET c.132-17C>T Benign ★★ same type

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-pro90ser (accessed [today's date]).

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