# NM_001082486.2(ACD):c.1299G>A (p.Arg433=)

https://sugi.bio/variant/acd-p-arg433

## Summary

**ACD p.Arg433= (c.1299G>A)** is classified **Conflicting classifications of pathogenicity** in ACD (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-01). Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs756845439 · 2 submitters · 2 linked conditions · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the ACD gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 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 | [ACD](https://sugi.bio/atlas/gene/ACD/) |
| Protein change (HGVS p.) | p.Arg433= |
| Coding change (HGVS c.) | c.1299G>A |
| MANE Select transcript | [NM_001082486](https://www.ncbi.nlm.nih.gov/nuccore/NM_001082486) |
| dbSNP | [rs756845439](https://www.ncbi.nlm.nih.gov/snp/rs756845439/) |
| Variant type | single nucleotide variant |
| Location | chr16:67657684-67657684 (GRCh38) |
| ClinVar | [VCV1775178](https://www.ncbi.nlm.nih.gov/clinvar/variation/1775178/) |

**All HGVS expressions:** `LRG_1237:g.8132G>A`, `LRG_1237t1:c.1299G>A`, `NC_000016.10:g.67657684C>T`, `NC_000016.9:g.67691587C>T`, `NG_042874.1:g.8132G>A`, `NG_054728.1:g.17766C>T`, `NM_001082486.2:c.1299G>A`, `NM_001410884.1:c.1212G>A`, `NM_022914.3:c.1290G>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 1.334, GERP -0.92, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.049**. 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, Δ0.24 acceptor loss), 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 **0.00223%** (eas) · 1/44,884 in the highest group · 1/1,461,782 alleles overall — very rare (popmax 0.00223%, eas).

*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}

**ACD** population constraint: LOEUF 0.921, pLI 4.3134e-10, missense-Z 1.066; ClinGen dosage — haploinsufficiency 0, 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):

- **ACD-related short telomere syndrome** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 63.09, 22% of residues very-high.

**28 experimental structure(s)** (PDB): [2I46](https://www.rcsb.org/structure/2I46), [5H65](https://www.rcsb.org/structure/5H65), [5I2X](https://www.rcsb.org/structure/5I2X), [5I2Y](https://www.rcsb.org/structure/5I2Y), [5UN7](https://www.rcsb.org/structure/5UN7), [5XYF](https://www.rcsb.org/structure/5XYF).

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

*Describes the biological roles of ACD (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:** ACD's established molecular role includes telomerase inhibitor activity.


### Pathways affected {#pathways}

ACD participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [Inhibition of DNA recombination at telomere](https://reactome.org/content/detail/R-HSA-9670095) | curated |
| [Packaging Of Telomere Ends](https://reactome.org/content/detail/R-HSA-171306) | curated |
| [Polymerase switching on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174411) | curated |
| [Processive synthesis on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174414) | curated |
| [Removal of the Flap Intermediate from the C-strand](https://reactome.org/content/detail/R-HSA-174437) | curated |
| [Telomere C-strand (Lagging Strand) Synthesis](https://reactome.org/content/detail/R-HSA-174417) | curated |
| [Telomere C-strand synthesis initiation](https://reactome.org/content/detail/R-HSA-174430) | curated |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |
| [Cleavage of the damaged purine](https://reactome.org/content/detail/R-HSA-110331) | electronic |
| [Cleavage of the damaged pyrimidine ](https://reactome.org/content/detail/R-HSA-110329) | electronic |
| [Meiotic synapsis](https://reactome.org/content/detail/R-HSA-1221632) | electronic |
| [Recognition and association of DNA glycosylase with site containing an affected purine](https://reactome.org/content/detail/R-HSA-110330) | electronic |
| [Recognition and association of DNA glycosylase with site containing an affected pyrimidine](https://reactome.org/content/detail/R-HSA-110328) | electronic |

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

**Molecular function:** telomerase inhibitor activity, telomeric repeat DNA binding, protein-containing complex binding, DNA polymerase binding.

**Biological process:** telomere maintenance, intracellular protein transport, telomere maintenance via telomerase, telomere capping, telomere assembly, negative regulation of telomere maintenance via telomerase.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-09-01.

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

**Submission history:** 2 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-07 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [dyskeratosis congenita, autosomal dominant 6](https://sugi.bio/atlas/disease/dyskeratosis-congenita-autosomal-dominant-6/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Dyskeratosis congenita, autosomal dominant 6.

## Similar variants {#similar}

Related ACD variant pages (same residue, condition, or type): [ACD p.Arg433Ser](/variant/acd-p-arg433ser), [ACD p.Arg433Trp](/variant/acd-p-arg433trp), [ACD c.645+2T>C](/variant/acd-c-645-plus-2t-c), [ACD c.99+5G>A](/variant/acd-c-99-plus-5g-a), [ACD c.-20C>T](/variant/acd-c-minus-20c-t), [ACD c.-24C>T](/variant/acd-c-minus-24c-t), [ACD c.-26T>G](/variant/acd-c-minus-26t-g), [ACD c.-29C>A](/variant/acd-c-minus-29c-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 1775178). 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.*