Is SET p.Val222Phe (c.664G>T) pathogenic?

SET p.Val222Phe (c.664G>T) is classified Uncertain significance in SET (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-21). AlphaMissense: likely pathogenic (0.9406); Very rare (popmax 0.00181%, amr).

How common is SET p.Val222Phe (c.664G>T) in the general population?

SET p.Val222Phe (c.664G>T) is very rare (popmax 0.00181%, amr) (gnomAD).

What do computational predictors say about SET p.Val222Phe (c.664G>T)?

AlphaMissense predicts likely pathogenic (score 0.9406) — an in-silico prediction, not a clinical call.

SET p.Val222Phe

c.664G>T · rs2490440641 · VCV3253464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9406 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00181%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9406	likely pathogenic
REVEL	0.237	benign-leaning
SaProt	LLR -14.94	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 4,260 bp · p 5.8e-31 · regional, not allelic
Overall
CADD	32.0	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 V235F vs ClinVar V222F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00181% Admixed American · 1/55,286 alleles

Overall 0.000139% 2/1,437,866 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00181%	55,286
European (non-Finnish)	8.56e-05%	1,168,312

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.Val222Phe
Coding: c.664G>T
MANE Select: NM_003011
dbSNP: rs2490440641
Type: single nucleotide variant
Location: chr9:128693896 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.62 · 3 PDB
Residue 222: the 'earmuff domain' region; an α-helix

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-val222phe (accessed [today's date]).

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