Is SETD5 p.Ala647fs (c.1937dup) pathogenic?

SETD5 p.Ala647fs (c.1937dup) is classified Likely pathogenic in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). Associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

SETD5 p.Ala647fs

Q: What condition is associated with SETD5 p.Ala647fs (c.1937dup)?

SETD5 p.Ala647fs (c.1937dup) is associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

c.1937dup · VCV4076162

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

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 15 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.2	GERP 0.42, phastCons 1

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

Variant & gene context

Gene: SETD5
Protein: p.Ala647fs
Coding: c.1937dup
MANE Select: NM_001080517
Type: Duplication
Location: chr3:9447839 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 647: the 'disordered' region; a UniProt-annotated variant site (in mrd23)

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

Disease context

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD5 p.Tyr1000fs Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Asn1059fs Likely pathogenic ★ same condition
SETD5 p.Asn814fs Pathogenic ★ same condition
SETD5 p.Gln534fs Likely pathogenic ★ same condition
SETD5 p.Gln801fs Pathogenic ★ same condition
SETD5 p.Gly344fs Pathogenic ★ same condition
SETD5 p.His966fs Likely pathogenic ★ same condition
SETD5 p.Lys600fs 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-ala647fs (accessed [today's date]).

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