Is SETD5 p.Ala1049fs (c.3145_3146delinsA) pathogenic?

SETD5 p.Ala1049fs (c.31453146delinsA) is classified Likely pathogenic in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-18). Associated with SETD5-related disorder.

What condition is associated with SETD5 p.Ala1049fs (c.3145_3146delinsA)?

SETD5 p.Ala1049fs (c.3145_3146delinsA) is associated with SETD5-related disorder (ClinVar).

SETD5 p.Ala1049fs

c.3145_3146delinsA · VCV4961128

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

SETD5-related 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 19 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.62	GERP -1.9, phastCons 0.99

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

Variant & gene context

Gene: SETD5
Protein: p.Ala1049fs
Coding: c.3145_3146delinsA
MANE Select: NM_001080517
Type: Indel
Location: chr3:9470879 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1049: 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

SETD5-related disorder

Similar variants

SETD5 p.Ala1049Gly Uncertain significance ★ ⚠ same residue
SETD5 p.Ala1049Pro Uncertain significance ★ ⚠ same residue
SETD5 p.Ala1049Thr Likely benign ★ same residue
SETD5 p.Arg1174Ter Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Arg445Ter Pathogenic ★★ same condition
SETD5 p.Arg768Ter Pathogenic ★★ same condition
SETD5 p.Gln1058Ter Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Gln272Ter 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/setd5-p-ala1049fs (accessed [today's date]).

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