Is SIM1 p.Val534fs (c.1598_1599dup) pathogenic?

SIM1 p.Val534fs (c.15981599dup) is classified Uncertain significance in SIM1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-15). Associated with SIM1-related disorder.

What condition is associated with SIM1 p.Val534fs (c.1598_1599dup)?

SIM1 p.Val534fs (c.1598_1599dup) is associated with SIM1-related disorder (ClinVar).

SIM1 p.Val534fs

c.1598_1599dup · VCV3345067

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

SIM1-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 LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (12 of 12) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1

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

Variant & gene context

Gene: SIM1
Protein: p.Val534fs
Coding: c.1598_1599dup
MANE Select: NM_005068
Type: Microsatellite
Location: chr6:100391062 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 534: the single-minded c-terminal domain; the 'disordered' region

Full SIM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SIM1-related disorder

Similar variants

SIM1 p.Leu265fs Likely pathogenic ★ same condition
SIM1 p.Phe56fs Likely pathogenic ★ same condition
SIM1 p.Arg374Trp Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser199Cys Uncertain significance ★★ same condition
SIM1 p.Gly480Ter Likely pathogenic ★ same condition
SIM1 p.Thr481fs Likely pathogenic ★ same condition
SIM1 c.-468+6T>A Uncertain significance ★ same condition
SIM1 p.Ala484Ser Uncertain significance ★ ⚠ 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/sim1-p-val534fs (accessed [today's date]).

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