Is SET p.Ile75= (c.225C>T) pathogenic?

SET p.Ile75= (c.225C>T) is classified Likely benign in SET (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-01). Ultra-rare (popmax 0.04%, amr).

How common is SET p.Ile75= (c.225C>T) in the general population?

SET p.Ile75= (c.225C>T) is ultra-rare (popmax 0.04%, amr) (gnomAD).

SET p.Ile75=

c.225C>T · rs148209973 · VCV3026167

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP -0.22, phastCons 1
Overall
CADD	15.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% Admixed American · 24/59,968 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00248% 40/1,613,716 alleles · ultra-rare exomes 38/1,461,576 · genomes 2/152,140 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,499
African / African-American	0.00668%	14,978
East Asian	0.00223%	44,904
Remaining individualsnot grpmax-eligible	0.0016%	62,472
South Asian	0.0011%	91,068
European (non-Finnish)	0.000678%	147,483

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.Ile75=
Coding: c.225C>T
MANE Select: NM_003011
dbSNP: rs148209973
Type: single nucleotide variant
Location: chr9:128691951 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.62 · 3 PDB
Residue 75: an α-helix; the 'dimerization' region

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

Similar variants

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
SET c.493-14C>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-ile75 (accessed [today's date]).

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