# NM_005164.4(ABCD2):c.1668T>G (p.Ser556Arg)

https://sugi.bio/variant/abcd2-p-ser556arg

## Summary

**ABCD2 p.Ser556Arg (c.1668T>G)** is classified **Uncertain significance** in ABCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-28). AlphaMissense: likely pathogenic (0.6604); Very rare (popmax 0.000254%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs773655555 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the ABCD2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [ABCD2](https://sugi.bio/atlas/gene/ABCD2/) |
| Protein change (HGVS p.) | p.Ser556Arg |
| Coding change (HGVS c.) | c.1668T>G |
| MANE Select transcript | [NM_005164](https://www.ncbi.nlm.nih.gov/nuccore/NM_005164) |
| dbSNP | [rs773655555](https://www.ncbi.nlm.nih.gov/snp/rs773655555/) |
| Variant type | single nucleotide variant |
| Location | chr12:39586276-39586276 (GRCh38) |
| ClinVar | [VCV2520289](https://www.ncbi.nlm.nih.gov/clinvar/variation/2520289/) |

**All HGVS expressions:** `NC_000012.11:g.39980078A>C`, `NC_000012.12:g.39586276A>C`, `NM_001412788.1:c.1668T>G`, `NM_001412789.1:c.1668T>G`, `NM_001412790.1:c.1668T>G`, `NM_001412791.1:c.1371T>G`, `NM_001412793.1:c.393T>G`, `NM_005164.4:c.1668T>G`, `NR_182045.1:n.1976T>G`, `NR_182046.1:n.1883T>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.6604)
- REVEL 0.652 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.106 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **acceptor gain** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.733, GERP -4.58, phastCons 1 — weakly conserved position
- CADD: **PHRED 22.5**. 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 0.88** across the covering region of the MANE Select transcript (39,553,915–39,604,006), spanning 50,091 bp. Chi-square p 0.028. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.29**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.29**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.00**.
- Pangolin: Δ**0.51** (gain), gain 0.51 / loss 0.28. 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 **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,474 in the highest group · 4/1,612,816 alleles overall — very rare (popmax 0.000254%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,446 |
| European (non-Finnish) (grpmax) | 0.000254% | 393,157 |

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}

**ABCD2** population constraint: LOEUF 0.714, pLI 7.7494e-05, missense-Z 2.3144. *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 **556** lies in the abc transporter domain.

AlphaFold model confidence (whole protein): pLDDT 81.65, 45% of residues very-high.

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

*Describes the biological roles of ABCD2 (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:** ABCD2's established molecular role includes ATP hydrolysis activity. p.Ser556Arg falls in the abc transporter domain.


### Pathways affected {#pathways}

ABCD2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |
| [Class I peroxisomal membrane protein import](https://reactome.org/content/detail/R-HSA-9603798) | curated |

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

**Molecular function:** ATP hydrolysis activity, ATPase-coupled transmembrane transporter activity, protein homodimerization activity, fatty acyl-CoA hydrolase activity.

**Biological process:** very long-chain fatty acid metabolic process, fatty acid beta-oxidation, positive regulation of fatty acid beta-oxidation, very long-chain fatty acid catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-28 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ABCD2 variant pages (same residue, condition, or type): [ABCD2 c.1878-18G>C](/variant/abcd2-c-1878-minus-18g-c), [ABCD2 p.Ala251Gly](/variant/abcd2-p-ala251gly), [ABCD2 p.Ala273Thr](/variant/abcd2-p-ala273thr), [ABCD2 p.Ala489Glu](/variant/abcd2-p-ala489glu), [ABCD2 p.Arg16Thr](/variant/abcd2-p-arg16thr), [ABCD2 p.Arg178Cys](/variant/abcd2-p-arg178cys), [ABCD2 p.Arg178His](/variant/abcd2-p-arg178his), [ABCD2 p.Arg337Cys](/variant/abcd2-p-arg337cys).

### 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 2520289). 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.*