Is SETD5 p.Ser1286fs (c.3856del) pathogenic?

SETD5 p.Ser1286fs (c.3856del) is classified Pathogenic/Likely pathogenic in SETD5 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-06-01). Very rare (popmax 0.0011%, sas); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with SETD5 p.Ser1286fs (c.3856del)?

SETD5 p.Ser1286fs (c.3856del) is associated with intellectual developmental disorder, autosomal dominant 45, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

How common is SETD5 p.Ser1286fs (c.3856del) in the general population?

SETD5 p.Ser1286fs (c.3856del) is very rare (popmax 0.0011%, sas) (gnomAD).

SETD5 p.Ser1286fs

c.3856del · rs587777329 · VCV127106

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

intellectual developmental disorder, autosomal dominant 45

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	escapes	premature termination codon in the last exon (23 of 23) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.29	GERP -2.4, phastCons 0.2

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Overall 0.000186% 3/1,613,986 alleles · very rare exomes 3/1,461,712 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
South Asiangrpmax	0.0011%	91,080
European (non-Finnish)	8.48e-05%	1,179,889

Remaining individuals 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: SETD5
Protein: p.Ser1286fs
Coding: c.3856del
MANE Select: NM_001080517
dbSNP: rs587777329
Type: Deletion
Location: chr3:9475618 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1286: a UniProt-annotated variant site (in mrd23); the 'disordered' region

Full SETD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder, autosomal dominant 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Similar variants

SETD5 p.Gln224fs Pathogenic ★★ same condition
SETD5 p.Ala641fs Likely pathogenic ★ same condition
SETD5 p.Arg290fs Pathogenic ★ same condition
SETD5 p.Arg589fs Pathogenic ★ same condition
SETD5 p.Asn345fs Pathogenic ★ same condition
SETD5 p.Asn573fs Likely pathogenic ★ same condition
SETD5 p.Asp1088fs Pathogenic ★ same condition
SETD5 p.Asp499fs 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/setd5-p-ser1286fs (accessed [today's date]).

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