# NM_001082486.2(ACD):c.198T>C (p.Ser66=)

https://sugi.bio/variant/acd-p-ser66

## Summary

**ACD p.Ser66= (c.198T>C)** is classified **Likely benign** in ACD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-01). Very rare (popmax 0.000255%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs968504696 · 3 submitters · 2 linked conditions · very rare (popmax 0.000255%, nfe)

## For patients & families {#patients}

This is a change in the ACD gene that is classified as likely benign — not considered disease-causing, 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 | [ACD](https://sugi.bio/atlas/gene/ACD/) |
| Protein change (HGVS p.) | p.Ser66= |
| Coding change (HGVS c.) | c.198T>C |
| MANE Select transcript | [NM_001082486](https://www.ncbi.nlm.nih.gov/nuccore/NM_001082486) |
| dbSNP | [rs968504696](https://www.ncbi.nlm.nih.gov/snp/rs968504696/) |
| Variant type | single nucleotide variant |
| Location | chr16:67659947-67659947 (GRCh38) |
| ClinVar | [VCV1741564](https://www.ncbi.nlm.nih.gov/clinvar/variation/1741564/) |

**All HGVS expressions:** `LRG_1237:g.5869T>C`, `LRG_1237t1:c.198T>C`, `NC_000016.10:g.67659947A>G`, `NC_000016.9:g.67693850A>G`, `NG_042874.1:g.5869T>C`, `NG_134089.1:g.458A>G`, `NM_001082486.2:c.198T>C`, `NM_001410884.1:c.198T>C`, `NM_022914.3:c.189T>C`

## 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 2.249, GERP -0.656, phastCons 0.992 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.41**. 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 assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000255%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,178,314 in the highest group · 3/1,455,334 alleles overall — very rare (popmax 0.000255%, 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.*

## 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}

Residue **66** lies in a β-strand.

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}

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

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2022–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-22 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-01 |

## 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, not provided, none provided.

## Similar variants {#similar}

Related ACD variant pages (same residue, condition, or type): [ACD p.Ser66Arg](/variant/acd-p-ser66arg), [ACD p.Ser66Gly](/variant/acd-p-ser66gly), [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 1741564). 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.*