Is SET p.Leu22Pro (c.65T>C) pathogenic?

SET p.Leu22Pro (c.65T>C) is classified Likely benign in SET (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-01). AlphaMissense: likely benign (0.043); Rare (popmax 0.868%, afr).

How common is SET p.Leu22Pro (c.65T>C) in the general population?

SET p.Leu22Pro (c.65T>C) is rare (popmax 0.868%, afr) (gnomAD).

What do computational predictors say about SET p.Leu22Pro (c.65T>C)?

AlphaMissense predicts likely benign (score 0.043) — an in-silico prediction, not a clinical call.

SET p.Leu22Pro

c.65T>C · rs138894709 · VCV3025809

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.043 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.868%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.043	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -3.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.51	GERP -3.1
Overall
CADD	2.301	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

Grpmax group 0.868% African / African-American · 637/73,360 alleles

Filtering AF 0.812% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.79%

Overall 0.0444% 692/1,557,540 alleles · rare exomes 330/1,405,282 · genomes 362/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.868%	115
Remaining individualsnot grpmax-eligible	0.038%	2,628
Admixed American	0.0272%	3,682
South Asian	0.0178%	5,618
European (non-Finnish)	0.000261%	383,531

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SET
Protein: p.Leu22Pro
Coding: c.65T>C
MANE Select: NM_003011 · reported on NM_001122821
dbSNP: rs138894709
Type: single nucleotide variant
Location: chr9:128683960 (GRCh38)

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

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-leu22pro (accessed [today's date]).

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