# NM_001921.3(DCTD):c.227A>T (p.Asp76Val)

https://sugi.bio/variant/dctd-p-asp76val

## Summary

**DCTD p.Asp76Val (c.227A>T)** is classified **Uncertain significance** in DCTD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: likely benign (0.2687); Very rare (popmax 0.01%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.01%, nfe)

## For patients & families {#patients}

This is a change in the DCTD 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 | [DCTD](https://sugi.bio/atlas/gene/DCTD/) |
| Protein change (HGVS p.) | p.Asp76Val |
| Coding change (HGVS c.) | c.227A>T |
| MANE Select transcript | [NM_001921](https://www.ncbi.nlm.nih.gov/nuccore/NM_001921) |
| Variant type | single nucleotide variant |
| Location | chr4:182914940-182914940 (GRCh38) |
| ClinVar | [VCV3271153](https://www.ncbi.nlm.nih.gov/clinvar/variation/3271153/) |

**All HGVS expressions:** `NC_000004.11:g.183836093T>A`, `NC_000004.12:g.182914940T>A`, `NM_001012732.2:c.260A>T`, `NM_001351743.2:c.227A>T`, `NM_001351744.2:c.227A>T`, `NM_001351745.2:c.227A>T`, `NM_001351747.2:c.227A>T`, `NM_001351748.2:c.227A>T`, `NM_001351750.2:c.227A>T`, `NM_001351753.2:c.227A>T`, `NM_001921.3:c.227A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2687)
- REVEL 0.45 (indeterminate)
- SaProt LLR -14.616 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 7.784, GERP 2.59, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.6**. 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 0.97** across the covering region of the MANE Select transcript (182,891,402–182,915,568), spanning 24,166 bp. Chi-square p 0.69. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>C, Δ0.28 donor 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 **0.01%** (nfe) · FAF95 0.00851% · FAF99 0.00795% · 118/1,180,058 in the highest group · 124/1,614,128 alleles overall — very rare (popmax 0.01%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.01% | 10,000 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,414 |

*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}

**DCTD** population constraint: LOEUF 1.924, pLI 2.1187e-07, missense-Z 0.3003. *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 **76** lies in the cmp/dcmp-type deaminase domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 94.43, 87% of residues very-high.

**1 experimental structure(s)** (PDB): [2W4L](https://www.rcsb.org/structure/2W4L).

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

*Describes the biological roles of DCTD (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:** DCTD's established molecular role includes identical protein binding. p.Asp76Val falls in the cmp/dcmp-type deaminase domain.


### Pathways affected {#pathways}

DCTD participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interconversion of nucleotide di- and triphosphates](https://reactome.org/content/detail/R-HSA-499943) | curated |

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

**Molecular function:** identical protein binding, 5-hydroxymethyl-dUMP N-hydrolase activity.

**Biological process:** nucleoside salvage.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-09.

**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 | 2024-04-09 |

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

## Similar variants {#similar}

Related DCTD variant pages (same residue, condition, or type): [DCTD p.Ala85=](/variant/dctd-p-ala85), [DCTD p.Ala23Gly](/variant/dctd-p-ala23gly), [DCTD p.Ala39Thr](/variant/dctd-p-ala39thr), [DCTD p.Arg153Trp](/variant/dctd-p-arg153trp), [DCTD p.Asn54Ser](/variant/dctd-p-asn54ser), [DCTD p.Asp97Glu](/variant/dctd-p-asp97glu), [DCTD p.Cys40Tyr](/variant/dctd-p-cys40tyr), [DCTD p.Glu137Lys](/variant/dctd-p-glu137lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3271153). 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.*