Is ETV6 p.Pro136Ala (c.406C>G) pathogenic?

ETV6 p.Pro136Ala (c.406C>G) is classified Uncertain significance in ETV6 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-26). AlphaMissense: likely benign (0.0841); Absent from gnomAD v4.1; Associated with thrombocytopenia 5.

What condition is associated with ETV6 p.Pro136Ala (c.406C>G)?

ETV6 p.Pro136Ala (c.406C>G) is associated with thrombocytopenia 5 (ClinVar).

How common is ETV6 p.Pro136Ala (c.406C>G) in the general population?

ETV6 p.Pro136Ala (c.406C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ETV6 p.Pro136Ala (c.406C>G)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

ETV6 p.Pro136Ala

Q: How is Familial platelet disorder with associated myeloid malignancy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.406C>G · rs1946587466 · VCV1030502

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombocytopenia 5

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 31 kb · p 0.2 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Pro136Ala
Coding: c.406C>G
MANE Select: NM_001987
dbSNP: rs1946587466
Type: single nucleotide variant
Location: chr12:11853504 (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

Disease context

thrombocytopenia 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial platelet disorder with associated myeloid malignancy (Orphanet):

Inheritance: Autosomal dominant

Similar variants

ETV6 p.Pro136Leu Uncertain significance ★★ ⚠ same residue
ETV6 p.Arg369Gln Pathogenic/Likely pathogenic ★★ same condition
ETV6 p.Arg369Trp Pathogenic/Likely pathogenic ★★ same condition
ETV6 p.Arg399Cys Pathogenic/Likely pathogenic ★★ same condition
ETV6 p.Arg399His Pathogenic/Likely pathogenic ★★ same condition
ETV6 p.Pro214Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
ETV6 p.Arg14Gln Uncertain significance ★★ ⚠ same condition
ETV6 p.Arg181Cys 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-pro136ala (accessed [today's date]).

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