# NM_000110.4(DPYD):c.1524G>A (p.Gln508=)

https://sugi.bio/variant/dpyd-p-gln508

## Summary

**DPYD p.Gln508= (c.1524G>A)** is classified **Uncertain significance** in DPYD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-26). Very rare (popmax 0.0067%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs775930761 · 2 submitters · 1 linked condition · very rare (popmax 0.0067%, nfe)

## For patients & families {#patients}

This is a change in the DPYD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [DPYD](https://sugi.bio/atlas/gene/DPYD/) |
| Protein change (HGVS p.) | p.Gln508= |
| Coding change (HGVS c.) | c.1524G>A |
| MANE Select transcript | [NM_000110](https://www.ncbi.nlm.nih.gov/nuccore/NM_000110) |
| dbSNP | [rs775930761](https://www.ncbi.nlm.nih.gov/snp/rs775930761/) |
| Variant type | single nucleotide variant |
| Location | chr1:97549560-97549560 (GRCh38) |
| ClinVar | [VCV2391206](https://www.ncbi.nlm.nih.gov/clinvar/variation/2391206/) |

**All HGVS expressions:** `LRG_722:g.376500G>A`, `LRG_722t1:c.1524G>A`, `NC_000001.10:g.98015116C>T`, `NC_000001.11:g.97549560C>T`, `NG_008807.2:g.376500G>A`, `NM_000110.4:c.1524G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.66) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.91, GERP 1.86, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.53**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.66**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.02**.
  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.*
- Pangolin: Δ**0.35** (loss), gain 0.28 / loss 0.35. 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 **0.0067%** (nfe) · FAF95 0.00546% · FAF99 0.00506% · 79/1,179,762 in the highest group · 90/1,613,604 alleles overall — very rare (popmax 0.0067%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,245 |
| European (non-Finnish) (grpmax) | 0.0067% | 14,934 |
| African / African-American | 0.00133% | 74,912 |

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}

**DPYD** population constraint: LOEUF 1.09, pLI 6.0188e-30, missense-Z 0.10047; ClinGen dosage — haploinsufficiency 30, 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 96.23, 95% of residues very-high.

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

*Describes the biological roles of DPYD (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:** DPYD's established molecular role includes dihydropyrimidine dehydrogenase (NADP+) activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Pyrimidine catabolism](https://reactome.org/content/detail/R-HSA-73621) | curated |

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

**Molecular function:** dihydropyrimidine dehydrogenase (NADP+) activity, protein homodimerization activity.

**Biological process:** purine nucleobase catabolic process, pyrimidine nucleobase catabolic process, thymine catabolic process, uracil catabolic process, thymidine catabolic process, xenobiotic catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-26.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-29 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-26 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided.

## Similar variants {#similar}

Related DPYD variant pages (same residue, condition, or type): [DPYD p.Ala513Val](/variant/dpyd-p-ala513val), [DPYD p.Ala664Ser](/variant/dpyd-p-ala664ser), [DPYD p.Arg332Gln](/variant/dpyd-p-arg332gln), [DPYD p.Arg410Gln](/variant/dpyd-p-arg410gln), [DPYD p.Arg692Gln](/variant/dpyd-p-arg692gln), [DPYD p.Glu13Lys](/variant/dpyd-p-glu13lys), [DPYD p.Glu950Lys](/variant/dpyd-p-glu950lys), [DPYD p.Gly748Ser](/variant/dpyd-p-gly748ser).

### 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 2391206). 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.*