Is SET p.Leu22= (c.66G>T) pathogenic?

SET p.Leu22= (c.66G>T) is classified Benign/Likely benign in SET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-26). Low-frequency (popmax 1.65%, afr).

How common is SET p.Leu22= (c.66G>T) in the general population?

SET p.Leu22= (c.66G>T) is low-frequency (popmax 1.65%, afr) (gnomAD).

SET p.Leu22=

c.66G>T · rs191311210 · VCV774204

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.65%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.65	GERP -4.8
Overall
CADD	0.889	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.65% African / African-American · 1,214/73,370 alleles

Filtering AF 1.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.55%

Overall 0.223% 3,465/1,557,270 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.65%	60
Middle Eastern	0.934%	107
Admixed American	0.608%	165
Ashkenazi Jewishnot grpmax-eligible	0.564%	177
Remaining individualsnot grpmax-eligible	0.46%	217
European (non-Finnish)	0.123%	814
South Asian	0.0214%	4,681
Finnishnot grpmax-eligible	0.0182%	5,493

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.Leu22=
Coding: c.66G>T
MANE Select: NM_003011 · reported on NM_001122821
dbSNP: rs191311210
Type: single nucleotide variant
Location: chr9:128683961 (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-leu22 (accessed [today's date]).

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