Is SIM1 p.Phe56fs (c.165_166dup) pathogenic?

SIM1 p.Phe56fs (c.165166dup) is classified Likely pathogenic in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). Associated with SIM1-related disorder.

What condition is associated with SIM1 p.Phe56fs (c.165_166dup)?

SIM1 p.Phe56fs (c.165_166dup) is associated with SIM1-related disorder (ClinVar).

SIM1 p.Phe56fs

c.165_166dup · VCV4293796

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

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	predicted	premature termination codon in exon 2 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1

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

Variant & gene context

Gene: SIM1
Protein: p.Phe56fs
Coding: c.165_166dup
MANE Select: NM_005068
Type: Microsatellite
Location: chr6:100463302 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70

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.Val534fs Uncertain significance 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-phe56fs (accessed [today's date]).

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