# NM_005068.3(SIM1):c.1422A>T (p.Ala474=)

https://sugi.bio/variant/sim1-p-ala474

## Summary

**SIM1 p.Ala474= (c.1422A>T)** is classified **Likely benign** in SIM1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-01). Very rare (popmax 0.000678%, nfe); Associated with SIM1-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs1005908784 · 1 submitter · 1 linked condition · very rare (popmax 0.000678%, nfe)

## For patients & families {#patients}

This is a change in the SIM1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to SIM1-related disorder.

*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.Ala474= |
| Coding change (HGVS c.) | c.1422A>T |
| MANE Select transcript | [NM_005068](https://www.ncbi.nlm.nih.gov/nuccore/NM_005068) |
| dbSNP | [rs1005908784](https://www.ncbi.nlm.nih.gov/snp/rs1005908784/) |
| Variant type | single nucleotide variant |
| Location | chr6:100393635-100393635 (GRCh38) |
| ClinVar | [VCV3058018](https://www.ncbi.nlm.nih.gov/clinvar/variation/3058018/) |

**All HGVS expressions:** `NC_000006.11:g.100841511T>A`, `NC_000006.12:g.100393635T>A`, `NG_008230.1:g.75041A>T`, `NG_008230.2:g.76286A>T`, `NM_001374769.1:c.1422A>T`, `NM_005068.3:c.1422A>T`, `NR_187148.1:n.150T>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.601, GERP -4.29 — fast-evolving / accelerated position
- CADD: **PHRED 6.977**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.25**, acceptor gain **0.00**, donor gain **0.05**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.05**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.20** (gain), gain 0.20 / loss 0.00. SpliceAI calls loss. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000678%** (nfe) · FAF95 0.000292% · FAF99 0.000211% · 8/1,179,962 in the highest group · 9/1,614,050 alleles overall — very rare (popmax 0.000678%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |
| European (non-Finnish) (grpmax) | 0.000678% | 147,495 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **474** lies in the single-minded c-terminal domain.

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

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2022-12-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-12-01 |

## Associated conditions {#conditions}

[SIM1-related disorder](https://sugi.bio/atlas/disease/sim1-related-disorder/).

**Reported phenotype names (ClinVar):** SIM1-related disorder, SIM1-related disorders, SIM1-related condition.

## Similar variants {#similar}

Related SIM1 variant pages (same residue, condition, or type): [SIM1 p.Arg374Trp](/variant/sim1-p-arg374trp), [SIM1 p.Ser199Cys](/variant/sim1-p-ser199cys), [SIM1 p.Gly480Ter](/variant/sim1-p-gly480ter), [SIM1 c.-468+6T>A](/variant/sim1-c-minus-468-plus-6t-a), [SIM1 p.Ala484Ser](/variant/sim1-p-ala484ser), [SIM1 p.Asn608Asp](/variant/sim1-p-asn608asp), [SIM1 p.Lys287Arg](/variant/sim1-p-lys287arg), [SIM1 p.Pro30Ala](/variant/sim1-p-pro30ala).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3058018). 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.*