Is SETD1A p.Pro1404fs (c.4209_4236del) pathogenic?

SETD1A p.Pro1404fs (c.42094236del) is classified Pathogenic in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). No allele count reported in gnomAD v4.1 (AN 1,494,194); Associated with neurodevelopmental disorder with speech impairment and dysmorphic facies.

What condition is associated with SETD1A p.Pro1404fs (c.4209_4236del)?

SETD1A p.Pro1404fs (c.4209_4236del) is associated with neurodevelopmental disorder with speech impairment and dysmorphic facies (ClinVar).

How common is SETD1A p.Pro1404fs (c.4209_4236del) in the general population?

SETD1A p.Pro1404fs (c.4209_4236del) is no allele count reported in gnomAD v4.1 (AN 1,494,194) (gnomAD).

SETD1A p.Pro1404fs

c.4209_4236del · VCV3336414

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,494,194)

Conditions

neurodevelopmental disorder with speech impairment and dysmorphic facies

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 14 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.6	GERP 0.63, phastCons 1
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CGCCGC)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

No allele count reported in gnomAD v4.1 (AN 1,494,194). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SETD1A
Protein: p.Pro1404fs
Coding: c.4209_4236del
MANE Select: NM_014712
Type: Deletion
Location: chr16:30979989 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 1404: the 'disordered' region; a UniProt-annotated variant site (in nedsid)

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

Disease context

neurodevelopmental disorder with speech impairment and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1A c.4582-2_4582-1del Pathogenic ★★ same condition
SETD1A p.Asp112fs Pathogenic ★ same condition
SETD1A p.Gln735fs Pathogenic ★ same condition
SETD1A p.Pro92fs Pathogenic ★ same condition
SETD1A p.Tyr382fs Likely pathogenic ★ same condition
SETD1A p.Pro1404Leu Uncertain significance ★ ⚠ same residue
SETD1A p.Gly535fs Pathogenic same condition
SETD1A p.Arg1571Ter Pathogenic/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-pro1404fs (accessed [today's date]).

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