# NM_000033.4(ABCD1):c.1983C>T (p.Pro661=)

https://sugi.bio/variant/abcd1-p-pro661

## Summary

**ABCD1 p.Pro661= (c.1983C>T)** is classified **Likely benign** in ABCD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-15). Very rare (popmax 0.000113%, nfe); Associated with adrenoleukodystrophy.

**At a glance:** Likely benign · review: Single submitter · rsID rs2522303742 · 1 submitter · 1 linked condition · very rare (popmax 0.000113%, nfe)

## For patients & families {#patients}

This is a change in the ABCD1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to adrenoleukodystrophy.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly |
| Prevalence | 1-9 / 1 000 000 (Israel) |
| Clinical trials | 48 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of X-linked adrenoleukodystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of vision — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Visual loss — Very frequent (99-80%)
- Atypical behavior — Very frequent (99-80%)
- Dementia — Very frequent (99-80%)
- Hyperactivity — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005758/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCD1](https://sugi.bio/atlas/gene/ABCD1/) |
| Protein change (HGVS p.) | p.Pro661= |
| Coding change (HGVS c.) | c.1983C>T |
| MANE Select transcript | [NM_000033](https://www.ncbi.nlm.nih.gov/nuccore/NM_000033) |
| dbSNP | [rs2522303742](https://www.ncbi.nlm.nih.gov/snp/rs2522303742/) |
| Variant type | single nucleotide variant |
| Location | chrX:153743338-153743338 (GRCh38) |
| ClinVar | [VCV2169214](https://www.ncbi.nlm.nih.gov/clinvar/variation/2169214/) |

**All HGVS expressions:** `LRG_1017:g.23471C>T`, `LRG_1017t1:c.1983C>T`, `NC_000023.10:g.153008792C>T`, `NC_000023.11:g.153743338C>T`, `NG_009022.2:g.23471C>T`, `NG_147801.1:g.708C>T`, `NG_147802.1:g.6C>T`, `NM_000033.4:c.1983C>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 0.146, GERP -3.14, phastCons 0.957 — weakly conserved position
- CADD: **PHRED 7.427**. 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 looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.000113%** (nfe) · 1/883,570 in the highest group · 1/1,187,238 alleles overall — very rare (popmax 0.000113%, nfe).

*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.*

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-07-15 |

## Associated conditions {#conditions}

[adrenoleukodystrophy](https://sugi.bio/atlas/disease/adrenoleukodystrophy/).

**Reported phenotype names (ClinVar):** Adrenoleukodystrophy, BRONZE SCHILDER DISEASE, X-Linked Adrenoleukodystrophy, SIEMERLING-CREUTZFELDT DISEASE, MELANODERMIC LEUKODYSTROPHY, ADDISON DISEASE AND CEREBRAL SCLEROSIS.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2169214). 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.*