# NM_001171.6(ABCC6):c.3458G>A (p.Arg1153His)

https://sugi.bio/variant/abcc6-p-arg1153his

## Summary

**ABCC6 p.Arg1153His (c.3458G>A)** is classified **Conflicting classifications of pathogenicity** in ABCC6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-06-14). AlphaMissense: likely benign (0.0722); Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs553479685 · 3 submitters · 4 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.016%, afr)

## For patients & families {#patients}

This is a change in the ABCC6 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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 | [ABCC6](https://sugi.bio/atlas/gene/ABCC6/) |
| Protein change (HGVS p.) | p.Arg1153His |
| Coding change (HGVS c.) | c.3458G>A |
| MANE Select transcript | [NM_001171](https://www.ncbi.nlm.nih.gov/nuccore/NM_001171) |
| dbSNP | [rs553479685](https://www.ncbi.nlm.nih.gov/snp/rs553479685/) |
| Variant type | single nucleotide variant |
| Location | chr16:16163041-16163041 (GRCh38) |
| ClinVar | [VCV1394987](https://www.ncbi.nlm.nih.gov/clinvar/variation/1394987/) |

**All HGVS expressions:** `LRG_1115:g.65577G>A`, `LRG_1115t1:c.3458G>A`, `NC_000016.10:g.16163041C>T`, `NC_000016.9:g.16256898C>T`, `NG_007558.3:g.65577G>A`, `NM_001171.5:c.3458G>A`, `NM_001171.6:c.3458G>A`, `NM_001351800.1:c.3116G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0722)
- REVEL 0.156 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.001 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.266, GERP -3.35 — weakly conserved position
- CADD: **PHRED 9.341**. 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 0.98** across the covering region of the MANE Select transcript (16,150,136–16,208,816), spanning 58,680 bp. Chi-square p 0.39. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 48 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.016%** (afr) · FAF95 0.0092% · FAF99 0.00735% · 12/75,060 in the highest group · 82/1,614,052 alleles overall — ultra-rare (popmax 0.016%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.016% | 6,255 |
| South Asian | 0.0154% | 6,505 |
| Admixed American | 0.00833% | 12,003 |
| European (non-Finnish) | 0.00398% | 25,107 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |
| East Asian | 0.00223% | 44,888 |
| Finnish (not grpmax-eligible) | 0.00157% | 63,878 |

*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}

**ABCC6** population constraint: LOEUF 0.917, pLI 1.2351e-33, missense-Z 1.031. *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):

- **inherited pseudoxanthoma elasticum** — Definitive (SD)

## Protein context {#protein}

Residue **1153** lies in the abc transmembrane type-1 2 domain.

AlphaFold model confidence (whole protein): pLDDT 81.32, 29% of residues very-high.

**4 experimental structure(s)** (PDB): [6BZR](https://www.rcsb.org/structure/6BZR), [6BZS](https://www.rcsb.org/structure/6BZS), [6NLO](https://www.rcsb.org/structure/6NLO), [6P7F](https://www.rcsb.org/structure/6P7F) — incl. mutant structure 6P7F.

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

*Describes the biological roles of ABCC6 (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:** ABCC6's established molecular role includes ATP binding. p.Arg1153His falls in the abc transmembrane type-1 2 domain. In Reactome, ABCC6 is annotated in disease pathway(s) including **Defective ABCC6 causes PXE**.

**Disease mechanism (Reactome):** ABCC6 loss or alteration is curated in [Defective ABCC6 causes PXE](https://reactome.org/content/detail/R-HSA-5690338).

### Pathways affected {#pathways}

ABCC6 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCC6 causes PXE](https://reactome.org/content/detail/R-HSA-5690338) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |

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

**Molecular function:** ATP binding, ABC-type glutathione S-conjugate transporter activity, ATPase-coupled transmembrane transporter activity.

**Biological process:** gene expression, ATP transport, ATP metabolic process, phosphate ion homeostasis, calcium ion homeostasis, leukotriene transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-06-14.

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

**Submission history:** 3 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-19 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-14 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [pseudoxanthoma elasticum, forme fruste](https://sugi.bio/atlas/disease/pseudoxanthoma-elasticum-forme-fruste/), [autosomal recessive inherited pseudoxanthoma elasticum](https://sugi.bio/atlas/disease/autosomal-recessive-inherited-pseudoxanthoma-elasticum/), [arterial calcification, generalized, of infancy, 2](https://sugi.bio/atlas/disease/arterial-calcification-generalized-of-infancy-2/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Arterial calcification, generalized, of infancy, 2, Autosomal recessive inherited pseudoxanthoma elasticum, Pseudoxanthoma elasticum, forme fruste, none provided, Pseudoxanthoma Elasticum, Incomplete, PSEUDOXANTHOMA ELASTICUM, HETEROZYGOUS.

## Similar variants {#similar}

Related ABCC6 variant pages (same residue, condition, or type): [ABCC6 p.Arg1153Cys](/variant/abcc6-p-arg1153cys), [ABCC6 p.Arg1153=](/variant/abcc6-p-arg1153), [ABCC6 c.1868-5T>G](/variant/abcc6-c-1868-minus-5t-g), [ABCC6 c.2591-1G>T](/variant/abcc6-c-2591-minus-1g-t), [ABCC6 c.2787+1G>T](/variant/abcc6-c-2787-plus-1g-t), [ABCC6 c.3507-1G>A](/variant/abcc6-c-3507-minus-1g-a), [ABCC6 c.37-1G>A](/variant/abcc6-c-37-minus-1g-a), [ABCC6 c.3736-1G>A](/variant/abcc6-c-3736-minus-1g-a).

### 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 1394987). 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.*