# NM_000047.3(ARSL):c.23G>C (p.Cys8Ser)

https://sugi.bio/variant/arsl-p-cys8ser

## Summary

**ARSL p.Cys8Ser (c.23G>C)** is classified **Uncertain significance** in ARSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-06-20). AlphaMissense: likely benign (0.079); Very rare (popmax 0.00415%, nfe); Associated with chondrodysplasia punctata, brachytelephalangic, autosomal.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1057521599 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00415%, nfe)

## For patients & families {#patients}

This is a change in the ARSL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to chondrodysplasia punctata, brachytelephalangic, autosomal.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015347/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ARSL](https://sugi.bio/atlas/gene/ARSL/) |
| Protein change (HGVS p.) | p.Cys8Ser |
| Coding change (HGVS c.) | c.23G>C |
| MANE Select transcript | [NM_000047](https://www.ncbi.nlm.nih.gov/nuccore/NM_000047) |
| dbSNP | [rs1057521599](https://www.ncbi.nlm.nih.gov/snp/rs1057521599/) |
| Variant type | single nucleotide variant |
| Location | chrX:2960378-2960378 (GRCh38) |
| ClinVar | [VCV383365](https://www.ncbi.nlm.nih.gov/clinvar/variation/383365/) |

**All HGVS expressions:** `NC_000023.10:g.2878419C>G`, `NC_000023.11:g.2960378C>G`, `NG_007091.1:g.8893G>C`, `NM_000047.3:c.23G>C`, `NM_001282628.2:c.-189G>C`, `NM_001282631.2:c.23G>C`, `NM_001369079.1:c.50G>C`, `NM_001369080.1:c.-189G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.079)
- REVEL 0.389 (indeterminate)
- SaProt LLR -5.07 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.74) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.341, GERP 0.581, phastCons 0.997 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.97**. 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.*
- Regional missense constraint: **o/e 0.63** across the covering region of the MANE Select transcript (2,934,835–2,960,400), spanning 25,565 bp. Chi-square p 8.2e-17. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.74**, donor loss **0.61**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.74**, donor loss **0.61**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.61** (loss), gain 0.00 / loss 0.61. Agrees with SpliceAI. 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 **0.00415%** (nfe) · FAF95 0.00303% · FAF99 0.00269% · 36/868,220 in the highest group · 38/1,173,549 alleles overall — very rare (popmax 0.00415%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00415% | 24,117 |
| East Asian | 0.003% | 33,288 |
| Remaining individuals (not grpmax-eligible) | 0.00216% | 46,393 |

*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}


Curated gene–disease validity (ClinGen):

- **X-linked chondrodysplasia punctata 1** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.57, 87% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ARSL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ARSL's established molecular role includes arylsulfatase activity.


### Pathways affected {#pathways}

ARSL participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [The activation of arylsulfatases](https://reactome.org/content/detail/R-HSA-1663150) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** arylsulfatase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-06-20.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 not provided).

**Submission history:** 3 submissions (2020–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-03-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-20 |
| GenomeConnect, ClinGen | not provided | no classification provided | phenotyping only |  |

## Associated conditions {#conditions}

[chondrodysplasia punctata, brachytelephalangic, autosomal](https://sugi.bio/atlas/disease/chondrodysplasia-punctata-brachytelephalangic-autosomal/), [X-linked chondrodysplasia punctata 1](https://sugi.bio/atlas/disease/x-linked-chondrodysplasia-punctata-1/).

**Reported phenotype names (ClinVar):** Chondrodysplasia punctata, brachytelephalangic, autosomal, X-linked chondrodysplasia punctata 1, not provided, BRACHYTELEPHALANGIC CHONDRODYSPLASIA PUNCTATA, none provided, Chondrodysplasia punctata, X-linked recessive, CHONDRODYSPLASIA PUNCTATA, BRACHYTELEPHALANGIC.

## Similar variants {#similar}

Related ARSL variant pages (same residue, condition, or type): [ARSL c.1289+1G>A](/variant/arsl-c-1289-plus-1g-a), [ARSL c.24-2A>G](/variant/arsl-c-24-minus-2a-g), [ARSL p.Gly117Arg](/variant/arsl-p-gly117arg), [ARSL p.Gly73Ser](/variant/arsl-p-gly73ser), [ARSL p.Ala182Thr](/variant/arsl-p-ala182thr), [ARSL p.Ala251Val](/variant/arsl-p-ala251val), [ARSL p.Ala45Val](/variant/arsl-p-ala45val), [ARSL p.Arg12Ser](/variant/arsl-p-arg12ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 383365). 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.*