Is SETD1B p.Pro1585fs (c.4749_4752del) pathogenic?

SETD1B p.Pro1585fs (c.47494752del) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-16). Ultra-rare (popmax 0.0768%, nfe); Associated with intellectual developmental disorder with seizures and language delay.

What condition is associated with SETD1B p.Pro1585fs (c.4749_4752del)?

SETD1B p.Pro1585fs (c.4749_4752del) is associated with intellectual developmental disorder with seizures and language delay (ClinVar).

How common is SETD1B p.Pro1585fs (c.4749_4752del) in the general population?

SETD1B p.Pro1585fs (c.4749_4752del) is ultra-rare (popmax 0.0768%, nfe) (gnomAD).

SETD1B p.Pro1585fs

c.4749_4752del · VCV3892408

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0768%, nfe)

Conditions

intellectual developmental disorder with seizures and language delay

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 12 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 1.2, phastCons 1
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CCCACC)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 0.0768% European (non-Finnish) · 846/1,100,982 alleles

Filtering AF 0.0725% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0708%

Overall 0.0634% 947/1,492,938 alleles · ultra-rare exomes 920/1,344,176 · genomes 27/148,762 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.112%	896
European (non-Finnish)grpmax	0.0768%	1,301
Remaining individualsnot grpmax-eligible	0.0567%	1,763
Ashkenazi Jewishnot grpmax-eligible	0.0356%	2,808
African / African-American	0.0324%	3,086
South Asian	0.0254%	3,936
Middle Eastern	0.0231%	4,322
Finnishnot grpmax-eligible	0.0107%	9,357
Admixed American	0.00991%	10,090
East Asian	0.00248%	40,248

Amish 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: SETD1B
Protein: p.Pro1585fs
Coding: c.4749_4752del
MANE Select: NM_001353345
Type: Deletion
Location: chr12:121823328 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1585: the 'disordered' region; a UniProt-annotated variant site (in iddseld)

Full SETD1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder with seizures and language delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1B p.Gly1392fs Pathogenic/Likely pathogenic ★★ same condition
SETD1B p.Arg1735fs Pathogenic ★ same condition
SETD1B p.Arg72fs Pathogenic ★ same condition
SETD1B p.Arg982fs Likely pathogenic ★ same condition
SETD1B p.Glu1199fs Likely pathogenic ★ same condition
SETD1B p.Glu94fs Likely pathogenic ★ same condition
SETD1B p.Gly362fs Likely pathogenic ★ same condition
SETD1B p.His720fs 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/setd1b-p-pro1585fs (accessed [today's date]).

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