# NM_001369268.1(ACAN):c.1929C>T (p.Cys643=)

https://sugi.bio/variant/acan-p-cys643

## Summary

**ACAN p.Cys643= (c.1929C>T)** is classified **Benign/Likely benign** in ACAN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). Rare (popmax 0.649%, sas).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs551265948 · 3 submitters · rare (popmax 0.649%, sas)

## For patients & families {#patients}

This is a change in the ACAN gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [ACAN](https://sugi.bio/atlas/gene/ACAN/) |
| Protein change (HGVS p.) | p.Cys643= |
| Coding change (HGVS c.) | c.1929C>T |
| MANE Select transcript | [NM_001369268](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369268) |
| dbSNP | [rs551265948](https://www.ncbi.nlm.nih.gov/snp/rs551265948/) |
| Variant type | single nucleotide variant |
| Location | chr15:88849634-88849634 (GRCh38) |
| ClinVar | [VCV2054597](https://www.ncbi.nlm.nih.gov/clinvar/variation/2054597/) |

**All HGVS expressions:** `NC_000015.10:g.88849634C>T`, `NC_000015.9:g.89392865C>T`, `NG_012794.1:g.51192C>T`, `NM_001135.4:c.1929C>T`, `NM_001369268.1:c.1929C>T`, `NM_001411096.1:c.1929C>T`, `NM_001411097.1:c.1929C>T`, `NM_013227.4:c.1929C>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 -10.069, GERP -3.77 — fast-evolving / accelerated position
- CADD: **PHRED 1.733**. 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 (C>A, Δ0.42 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 (gnomAD v4.1): grpmax **0.649%** (sas) · FAF95 0.605% · FAF99 0.588% · 590/90,968 in the highest group · 624/1,612,708 alleles overall — rare (popmax 0.649%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.649% | 154 |
| Remaining individuals (not grpmax-eligible) | 0.0432% | 2,313 |
| East Asian | 0.00223% | 44,828 |
| European (non-Finnish) | 0.000509% | 196,600 |

*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}

**ACAN** population constraint: LOEUF 0.377, pLI 1, missense-Z 0.32052. *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):

- **ACAN-related short stature spectrum** — Definitive (AD)

## Protein context {#protein}

Residue **643** lies in a disulfide bond; the 'g2-b'' region; the link 4 domain.

AlphaFold model confidence (whole protein): pLDDT 53.32, 17% of residues very-high.

**4 experimental structure(s)** (PDB): [4MD4](https://www.rcsb.org/structure/4MD4), [7RDV](https://www.rcsb.org/structure/7RDV), [9DFF](https://www.rcsb.org/structure/9DFF), [9DFT](https://www.rcsb.org/structure/9DFT).

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

*Describes the biological roles of ACAN (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:** p.Cys643= falls in the g2-b region. In Reactome, ACAN is annotated in disease pathway(s) including **Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)**, **Defective CHST6 causes MCDC1**.

**Disease mechanism (Reactome):** ACAN loss or alteration is curated in [Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)](https://reactome.org/content/detail/R-HSA-3656244), [Defective CHST6 causes MCDC1](https://reactome.org/content/detail/R-HSA-3656225), [Defective ST3GAL3 causes MCT12 and EIEE15](https://reactome.org/content/detail/R-HSA-3656243).

### Pathways affected {#pathways}

ACAN participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)](https://reactome.org/content/detail/R-HSA-3656244) | curated |
| ⚕ [Defective CHST6 causes MCDC1](https://reactome.org/content/detail/R-HSA-3656225) | curated |
| ⚕ [Defective ST3GAL3 causes MCT12 and EIEE15](https://reactome.org/content/detail/R-HSA-3656243) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Keratan sulfate biosynthesis](https://reactome.org/content/detail/R-HSA-2022854) | curated |
| [Keratan sulfate degradation](https://reactome.org/content/detail/R-HSA-2022857) | curated |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | electronic |

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

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

**Submission history:** 3 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-31 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-20 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Same-residue context {#hotspot}

Residue **643** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ACAN p.Cys643Ter](/variant/acan-p-cys643ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ACAN variant pages (same residue, condition, or type): [ACAN p.Cys643Ter](/variant/acan-p-cys643ter), [ACAN p.Cys643Arg](/variant/acan-p-cys643arg), [ACAN c.1733-2A>G](/variant/acan-c-1733-minus-2a-g), [ACAN c.630-13G>A](/variant/acan-c-630-minus-13g-a), [ACAN c.7302+1G>A](/variant/acan-c-7302-plus-1g-a), [ACAN p.Arg236Ter](/variant/acan-p-arg236ter), [ACAN p.Arg386Ter](/variant/acan-p-arg386ter), [ACAN p.Arg394Ter](/variant/acan-p-arg394ter).

### 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 2054597). 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.*