Is ETV6 p.Pro253= (c.759G>A) pathogenic?

ETV6 p.Pro253= (c.759G>A) is classified Likely benign in ETV6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-04). Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with ETV6 p.Pro253= (c.759G>A)?

ETV6 p.Pro253= (c.759G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ETV6 p.Pro253= (c.759G>A) in the general population?

ETV6 p.Pro253= (c.759G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

ETV6 p.Pro253=

c.759G>A · rs371171278 · VCV1989520

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Inborn genetic diseases

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 -0.18	GERP -0.59, phastCons 0.033
Overall
CADD	11.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,076 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00118% 19/1,613,768 alleles · very rare exomes 16/1,461,684 · genomes 3/152,084 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,538
European (non-Finnish)	0.00136%	73,752
African / African-American	0.00134%	74,892

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.Pro253=
Coding: c.759G>A
MANE Select: NM_001987
dbSNP: rs371171278
Type: single nucleotide variant
Location: chr12:11869719 (GRCh38)
Gene constraint: LOEUF 0.44 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.61 · 43 PDB
Residue 253: 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.Pro253Leu Uncertain significance ★★ ⚠ same residue
ETV6 p.Pro253Arg Uncertain significance ★ ⚠ same residue
ETV6 p.Pro253Ser 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
ETV6 p.Ala67Asp 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-pro253 (accessed [today's date]).

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