Is ETS1 p.Pro194Ser (c.580C>T) pathogenic?

ETS1 p.Pro194Ser (c.580C>T) is classified Uncertain significance in ETS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.074); Very rare (popmax 0.00017%, nfe).

How common is ETS1 p.Pro194Ser (c.580C>T) in the general population?

ETS1 p.Pro194Ser (c.580C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ETS1 p.Pro194Ser (c.580C>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

ETS1 p.Pro194Ser

c.580C>T · VCV3846398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -5.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 5,627 bp · p 3.8e-08 · regional, not allelic
Overall
CADD	22.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P150S vs ClinVar P194S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,998 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,611,834 alleles · very rare exomes 3/1,459,572 · genomes 0/152,262 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,432
European (non-Finnish)grpmax	0.00017%	588,998

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ETS1
Protein: p.Pro194Ser
Coding: c.580C>T
MANE Select: NM_001143820
Type: single nucleotide variant
Location: chr11:128486102 (GRCh38)
Gene constraint: LOEUF 0.393 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.95 · 21 PDB
Residue 150 UniProt numbering: the 'activation domain; required for transcription activation' region

Full ETS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ETS1 c.*1736A>G Benign ★★ same type
ETS1 p.Ala151Thr Likely benign ★★ same type
ETS1 p.Arg307= Benign ★★ same type
ETS1 p.Pro12= Benign ★★ same type
ETS1 p.Ser200= Benign ★★ same type
ETS1 p.Arg35Ter Likely pathogenic ★ same type
ETS1 p.Ala337Ser Uncertain significance ★ ⚠ same type
ETS1 p.Ala338Val Uncertain significance ★ ⚠ 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/ets1-p-pro194ser (accessed [today's date]).

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