# NM_005068.3(SIM1):c.1641C>T (p.Asp547=)

https://sugi.bio/variant/sim1-p-asp547

## Summary

**SIM1 p.Asp547= (c.1641C>T)** is classified **Uncertain significance** in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-10-19). No allele count reported in gnomAD v4.1 (AN 1,614,032).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1582598833 · 1 submitter · no allele count reported in gnomAD v4.1 (AN 1,614,032)

## For patients & families {#patients}

This is a change in the SIM1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SIM1](https://sugi.bio/atlas/gene/SIM1/) |
| Protein change (HGVS p.) | p.Asp547= |
| Coding change (HGVS c.) | c.1641C>T |
| MANE Select transcript | [NM_005068](https://www.ncbi.nlm.nih.gov/nuccore/NM_005068) |
| dbSNP | [rs1582598833](https://www.ncbi.nlm.nih.gov/snp/rs1582598833/) |
| Variant type | single nucleotide variant |
| Location | chr6:100391021-100391021 (GRCh38) |
| ClinVar | [VCV1336902](https://www.ncbi.nlm.nih.gov/clinvar/variation/1336902/) |

**All HGVS expressions:** `NC_000006.11:g.100838897G>A`, `NC_000006.12:g.100391021G>A`, `NG_008230.1:g.77655C>T`, `NM_001374769.1:c.1641C>T`, `NM_005068.3:c.1641C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.743, GERP -2.66, phastCons 1 — weakly conserved position
- CADD: **PHRED 5.002**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.69 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,614,032)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**SIM1** population constraint: LOEUF 0.332, pLI 1, missense-Z 1.0526; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **547** lies in the single-minded c-terminal domain; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 60.70, 31% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-10-19.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-19 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related SIM1 variant pages (same residue, condition, or type): [SIM1 p.Asp547Glu](/variant/sim1-p-asp547glu), [SIM1 p.Cys434Ter](/variant/sim1-p-cys434ter), [SIM1 p.Ala495Gly](/variant/sim1-p-ala495gly), [SIM1 p.Arg374Trp](/variant/sim1-p-arg374trp), [SIM1 p.Arg548Gln](/variant/sim1-p-arg548gln), [SIM1 p.Arg550His](/variant/sim1-p-arg550his), [SIM1 p.Cys605Tyr](/variant/sim1-p-cys605tyr), [SIM1 p.Gln704Leu](/variant/sim1-p-gln704leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1336902). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*