Is ETV4 p.Pro424Ser (c.1270C>T) pathogenic?

ETV4 p.Pro424Ser (c.1270C>T) is classified Uncertain significance in ETV4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.9655); Very rare (popmax 0.00333%, amr).

How common is ETV4 p.Pro424Ser (c.1270C>T) in the general population?

ETV4 p.Pro424Ser (c.1270C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ETV4 p.Pro424Ser (c.1270C>T)?

AlphaMissense predicts likely pathogenic (score 0.9655) — an in-silico prediction, not a clinical call.

ETV4 p.Pro424Ser

c.1270C>T · VCV4251389

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.9655	likely pathogenic
REVEL	0.486	indeterminate
SaProt	LLR -14.49	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 10	GERP 2.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.059 · regional, not allelic
Overall
CADD	26.1	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

Grpmax group 0.00333% Admixed American · 2/60,016 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,614,134 alleles · very rare exomes 4/1,461,862 · genomes 0/152,272 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,008
European (non-Finnish)	0.000169%	590,005

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: ETV4
Protein: p.Pro424Ser
Coding: c.1270C>T
MANE Select: NM_001079675
Type: single nucleotide variant
Location: chr17:43528704 (GRCh38)

Full ETV4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/etv4-p-pro424ser (accessed [today's date]).

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