# NM_014918.5(CHSY1):c.1566G>A (p.Ser522=)

https://sugi.bio/variant/chsy1-p-ser522

## Summary

**CHSY1 p.Ser522= (c.1566G>A)** is classified **Benign/Likely benign** in CHSY1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Low-frequency (popmax 2.25%, afr); Associated with temtamy preaxial brachydactyly syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs74784454 · 3 submitters · 1 linked condition · low-frequency (popmax 2.25%, afr)

## For patients & families {#patients}

This is a change in the CHSY1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to temtamy preaxial brachydactyly syndrome.

*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/0009679/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHSY1](https://sugi.bio/atlas/gene/CHSY1/) |
| Protein change (HGVS p.) | p.Ser522= |
| Coding change (HGVS c.) | c.1566G>A |
| MANE Select transcript | [NM_014918](https://www.ncbi.nlm.nih.gov/nuccore/NM_014918) |
| dbSNP | [rs74784454](https://www.ncbi.nlm.nih.gov/snp/rs74784454/) |
| Variant type | single nucleotide variant |
| Location | chr15:101178231-101178231 (GRCh38) |
| ClinVar | [VCV786869](https://www.ncbi.nlm.nih.gov/clinvar/variation/786869/) |

**All HGVS expressions:** `NC_000015.10:g.101178231C>T`, `NC_000015.9:g.101718436C>T`, `NG_031908.1:g.78702G>A`, `NM_014918.5:c.1566G>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 (below), not from a missing predictor score.
- Conservation: phyloP -3.642, GERP -3.79 — fast-evolving / accelerated position
- CADD: **PHRED 0.196**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **2.25%** (afr) · FAF95 2.16% · FAF99 2.12% · 1,685/75,040 in the highest group · 2,867/1,614,190 alleles overall — low-frequency (popmax 2.25%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.25% | 45 |
| Middle Eastern | 0.462% | 216 |
| Remaining individuals (not grpmax-eligible) | 0.261% | 384 |
| Admixed American | 0.198% | 504 |
| South Asian | 0.0889% | 1,124 |
| European (non-Finnish) | 0.0658% | 1,521 |
| Finnish (not grpmax-eligible) | 0.0203% | 4,926 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| East Asian | 0.00223% | 44,890 |

*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}

**CHSY1** population constraint: LOEUF 0.357, pLI 1, missense-Z 0.87685; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **temtamy preaxial brachydactyly syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.20, 59% of residues very-high.

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

*Describes the biological roles of CHSY1 (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:** CHSY1's established molecular role includes glucuronosyl-N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase activity. In Reactome, CHSY1 is annotated in disease pathway(s) including **Defective CHSY1 causes TPBS**.

**Disease mechanism (Reactome):** CHSY1 loss or alteration is curated in [Defective CHSY1 causes TPBS](https://reactome.org/content/detail/R-HSA-3595177).

### Pathways affected {#pathways}

CHSY1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CHSY1 causes TPBS](https://reactome.org/content/detail/R-HSA-3595177) | other |
| [CS-GAG biosynthesis](https://reactome.org/content/detail/R-HSA-2022870) | other |

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

**Molecular function:** glucuronosyl-N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase activity, N-acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase activity.

**Biological process:** negative regulation of ossification, chondroitin sulfate proteoglycan biosynthetic process.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-13 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |

## Associated conditions {#conditions}

[temtamy preaxial brachydactyly syndrome](https://sugi.bio/atlas/disease/temtamy-preaxial-brachydactyly-syndrome/).

**Reported phenotype names (ClinVar):** Temtamy preaxial brachydactyly syndrome, not provided, none provided.

## Similar variants {#similar}

Related CHSY1 variant pages (same residue, condition, or type): [CHSY1 p.Ser522Pro](/variant/chsy1-p-ser522pro), [CHSY1 p.Ala263Ser](/variant/chsy1-p-ala263ser), [CHSY1 p.Ala61Val](/variant/chsy1-p-ala61val), [CHSY1 p.Arg180His](/variant/chsy1-p-arg180his), [CHSY1 p.Arg229Trp](/variant/chsy1-p-arg229trp), [CHSY1 p.Arg233Trp](/variant/chsy1-p-arg233trp), [CHSY1 p.Arg244Trp](/variant/chsy1-p-arg244trp), [CHSY1 p.Arg322His](/variant/chsy1-p-arg322his).

### 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 786869). 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.*