Is ETV6 p.Pro223= (c.669G>T) pathogenic?

ETV6 p.Pro223= (c.669G>T) is classified Likely benign in ETV6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). Very rare (popmax 0.00229%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ETV6 p.Pro223= (c.669G>T)?

ETV6 p.Pro223= (c.669G>T) is associated with Inborn genetic diseases (ClinVar).

How common is ETV6 p.Pro223= (c.669G>T) in the general population?

ETV6 p.Pro223= (c.669G>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

ETV6 p.Pro223=

c.669G>T · rs746757399 · VCV1337616

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.36	GERP -1.6, phastCons 0.055
Overall
CADD	6.413	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% European (non-Finnish) · 27/1,180,036 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.0018% 29/1,614,054 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,705
Admixed American	0.00167%	60,002
African / African-American	0.00133%	74,926

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: ETV6
Protein: p.Pro223=
Coding: c.669G>T
MANE Select: NM_001987
dbSNP: rs746757399
Type: single nucleotide variant
Location: chr12:11869629 (GRCh38)
Gene constraint: LOEUF 0.44 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.61 · 43 PDB
Residue 223: the 'disordered' region

Full ETV6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ETV6 p.Pro223Ala Uncertain significance ★ ⚠ same residue
ETV6 p.Pro223Gln Uncertain significance ★ ⚠ same residue
ETV6 p.Pro223Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ETV6 p.Pro223Thr Uncertain significance ★ ⚠ same residue
ETV6 p.Arg359Ter Pathogenic ★★ same condition
ETV6 p.Arg369Gln Pathogenic/Likely pathogenic ★★ same condition
ETV6 c.1010-3T>C Uncertain significance ★★ same condition
ETV6 p.Ala247Gly Uncertain significance ★★ ⚠ same condition

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/etv6-p-pro223 (accessed [today's date]).

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