Is SETD1A p.Pro609fs (c.1826del) pathogenic?

SETD1A p.Pro609fs (c.1826del) is classified Likely pathogenic in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-13). Very rare (popmax 0.000619%, nfe); Associated with SETD1A-related disorder.

What condition is associated with SETD1A p.Pro609fs (c.1826del)?

SETD1A p.Pro609fs (c.1826del) is associated with SETD1A-related disorder (ClinVar).

How common is SETD1A p.Pro609fs (c.1826del) in the general population?

SETD1A p.Pro609fs (c.1826del) is very rare (popmax 0.000619%, nfe) (gnomAD).

SETD1A p.Pro609fs

c.1826del · VCV4929472

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000619%, nfe)

Conditions

SETD1A-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 8 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -6.5	GERP -3.5
Region caveats
Repeat context	tandem	(CCT)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000619% European (non-Finnish) · 2/323,174 alleles

Filtering AF 0.000103% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.9e-05%

Overall 0.00045% 2/444,078 alleles · very rare exomes 2/429,616 · genomes 0/14,462 · joint denominator

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: SETD1A
Protein: p.Pro609fs
Coding: c.1826del
MANE Select: NM_014712
Type: Deletion
Location: chr16:30965703 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 609: a UniProt-annotated variant site (in nedsid); the 'disordered' region

Full SETD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SETD1A-related disorder

Similar variants

SETD1A p.Ala1323fs Likely pathogenic ★ same condition
SETD1A p.Gly206fs Likely pathogenic ★ same condition
SETD1A p.Pro654fs Likely pathogenic ★ same condition
SETD1A p.Phe1170del Uncertain significance same condition
SETD1A p.Leu669Phe Uncertain significance ★★ ⚠ same condition
SETD1A p.Pro449Ala Uncertain significance ★★ ⚠ same condition
SETD1A p.Cys1697Arg Likely pathogenic ★ same condition
SETD1A p.Glu1345Ter Likely pathogenic ★ 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/setd1a-p-pro609fs (accessed [today's date]).

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