Is SETD1B p.His8fs (c.22dup) pathogenic?

SETD1B p.His8fs (c.22dup) is classified Pathogenic in SETD1B (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-11-08). Very rare (popmax 0.00611%, amr); Associated with neurodevelopmental disorder.

What condition is associated with SETD1B p.His8fs (c.22dup)?

SETD1B p.His8fs (c.22dup) is associated with neurodevelopmental disorder, intellectual developmental disorder with seizures and language delay (ClinVar).

How common is SETD1B p.His8fs (c.22dup) in the general population?

SETD1B p.His8fs (c.22dup) is very rare (popmax 0.00611%, amr) (gnomAD).

SETD1B p.His8fs

c.22dup · rs777278685 · VCV2236999

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00611%, amr)

Conditions

neurodevelopmental 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 2 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.3	GERP 0.87, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CAC)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 0.00611% Admixed American · 3/49,060 alleles

Filtering AF 0.00162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00085%

Overall 0.00557% 85/1,527,204 alleles · very rare exomes 84/1,386,942 · genomes 1/140,262 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.117%	856
Admixed Americangrpmax	0.00611%	16,353
Remaining individualsnot grpmax-eligible	0.00506%	19,770
African / African-American	0.00293%	34,134
European (non-Finnish)	0.00088%	113,581

Finnish 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.His8fs
Coding: c.22dup
MANE Select: NM_001353345
dbSNP: rs777278685
Type: Duplication
Location: chr12:121804751 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 8: the 'disordered' region

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

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual developmental disorder with seizures and language delay

Similar variants

SETD1B p.Asp458fs Pathogenic ★★ same condition
SETD1B p.His8Pro Benign/Likely benign ★★ same residue
SETD1B p.Ala1776fs Pathogenic ★ same condition
SETD1B p.Arg511fs Pathogenic ★ same condition
SETD1B p.Asn1709fs Likely pathogenic ★ same condition
SETD1B p.Asp1736fs Likely pathogenic ★ same condition
SETD1B p.Gln200fs Pathogenic ★ same condition
SETD1B p.Glu412fs 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-his8fs (accessed [today's date]).

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