Is SETD1B p.Pro694fs (c.2078dup) pathogenic?

SETD1B p.Pro694fs (c.2078dup) is classified Pathogenic in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-28). Ultra-rare (popmax 0.0611%, nfe).

How common is SETD1B p.Pro694fs (c.2078dup) in the general population?

SETD1B p.Pro694fs (c.2078dup) is ultra-rare (popmax 0.0611%, nfe) (gnomAD).

SETD1B p.Pro694fs

c.2078dup · VCV4071616

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0611%, nfe)

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 7 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.032	GERP -2.7
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0611% European (non-Finnish) · 443/724,750 alleles

Filtering AF 0.0564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0545%

Overall 0.0555% 506/912,240 alleles · ultra-rare exomes 506/892,990 · genomes 0/19,250 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0611%	1,636
Remaining individualsnot grpmax-eligible	0.0578%	1,732
Admixed American	0.052%	1,922
Middle Eastern	0.0384%	2,602
Ashkenazi Jewishnot grpmax-eligible	0.0331%	3,024
East Asian	0.0323%	3,092
African / African-American	0.0292%	3,429
South Asian	0.0186%	5,388
Finnishnot grpmax-eligible	0.00934%	10,702

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.Pro694fs
Coding: c.2078dup
MANE Select: NM_001353345
Type: Duplication
Location: chr12:121814285 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 694: the 'disordered' region

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

Similar variants

SETD1B p.Asp458fs Pathogenic ★★ same type
SETD1B p.His8fs Pathogenic ★★ same type
SETD1B p.Pro924_Lys925insGluAspArgProLysPro Uncertain significance ★★ same type
SETD1B p.Ala1776fs Pathogenic ★ same type
SETD1B p.Ala320fs Likely pathogenic ★ same type
SETD1B p.Arg511fs Pathogenic ★ same type
SETD1B p.Asn1709fs Likely pathogenic ★ same type
SETD1B p.Asp1736fs Likely pathogenic ★ 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/setd1b-p-pro694fs (accessed [today's date]).

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