Is ETV6 p.Pro423Ser (c.1267C>T) pathogenic?

ETV6 p.Pro423Ser (c.1267C>T) is classified Uncertain significance in ETV6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.9965); Absent from gnomAD v4.1.

How common is ETV6 p.Pro423Ser (c.1267C>T) in the general population?

ETV6 p.Pro423Ser (c.1267C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ETV6 p.Pro423Ser (c.1267C>T)?

AlphaMissense predicts likely pathogenic (score 0.9965) — an in-silico prediction, not a clinical call.

ETV6 p.Pro423Ser

c.1267C>T · rs2498210952 · VCV2786243

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9965 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9965	likely pathogenic
REVEL	0.731	pathogenic-leaning
SaProt	LLR -11.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.36	unconstrained · MANE · 21 kb · p 5.2e-15 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ETV6
Protein: p.Pro423Ser
Coding: c.1267C>T
MANE Select: NM_001987
dbSNP: rs2498210952
Type: single nucleotide variant
Location: chr12:11890954 (GRCh38)
Gene constraint: LOEUF 0.44 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.61 · 43 PDB

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

Similar variants

ETV6 p.Pro423= Likely benign ★ same residue
ETV6 p.Arg105Ter Pathogenic/Likely pathogenic ★★ same type
ETV6 p.Arg339Ter Pathogenic ★★ same type
ETV6 p.Arg359Ter Pathogenic ★★ same type
ETV6 p.Arg369Gln Pathogenic/Likely pathogenic ★★ same type
ETV6 p.Arg369Trp Pathogenic/Likely pathogenic ★★ same type
ETV6 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same type
ETV6 p.Arg399Cys Pathogenic/Likely pathogenic ★★ 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/etv6-p-pro423ser (accessed [today's date]).

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