# NM_001917.5(DAO):c.309G>A (p.Pro103=)

https://sugi.bio/variant/dao-p-pro103

## Summary

**DAO p.Pro103= (c.309G>A)** is classified **Uncertain significance** in DAO (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). Ultra-rare (popmax 0.0111%, nfe); Associated with DAO-related disorder.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs147144733 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0111%, nfe)

## For patients & families {#patients}

This is a change in the DAO gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to DAO-related disorder.

*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 | [DAO](https://sugi.bio/atlas/gene/DAO/) |
| Protein change (HGVS p.) | p.Pro103= |
| Coding change (HGVS c.) | c.309G>A |
| MANE Select transcript | [NM_001917](https://www.ncbi.nlm.nih.gov/nuccore/NM_001917) |
| dbSNP | [rs147144733](https://www.ncbi.nlm.nih.gov/snp/rs147144733/) |
| Variant type | single nucleotide variant |
| Location | chr12:108887564-108887564 (GRCh38) |
| ClinVar | [VCV2634811](https://www.ncbi.nlm.nih.gov/clinvar/variation/2634811/) |

**All HGVS expressions:** `NC_000012.11:g.109281340G>A`, `NC_000012.12:g.108887564G>A`, `NG_023236.1:g.12484G>A`, `NM_001413634.1:c.309G>A`, `NM_001413635.1:c.309G>A`, `NM_001917.5:c.309G>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 0.75) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.883, GERP 0.301, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.86**. 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 **0.75**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.75**, acceptor gain **0.00**, donor gain **0.02**.
- Pangolin: Δ**0.57** (loss), gain 0.06 / loss 0.57. 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 **0.0111%** (nfe) · FAF95 0.00956% · FAF99 0.009% · 131/1,174,974 in the highest group · 141/1,608,404 alleles overall — ultra-rare (popmax 0.0111%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,902 |
| European (non-Finnish) (grpmax) | 0.0111% | 8,969 |
| Admixed American | 0.00167% | 59,990 |
| African / African-American | 0.00134% | 74,740 |
| South Asian | 0.0011% | 90,970 |

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}

**DAO** population constraint: LOEUF 1.222, pLI 7.8742e-15, missense-Z 0.39362. *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):

- **amyotrophic lateral sclerosis** — Refuted (AD)

## Protein context {#protein}

Residue **103** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.26, 94% of residues very-high.

**22 experimental structure(s)** (PDB): [2DU8](https://www.rcsb.org/structure/2DU8), [2E48](https://www.rcsb.org/structure/2E48), [2E49](https://www.rcsb.org/structure/2E49), [2E4A](https://www.rcsb.org/structure/2E4A), [2E82](https://www.rcsb.org/structure/2E82), [3CUK](https://www.rcsb.org/structure/3CUK) — incl. mutant structure 6KBP.

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

*Describes the biological roles of DAO (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:** DAO's established molecular role includes D-amino-acid oxidase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glyoxylate metabolism and glycine degradation](https://reactome.org/content/detail/R-HSA-389661) | curated |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |

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

**Molecular function:** D-amino-acid oxidase activity, identical protein binding, FAD binding.

**Biological process:** L-proline catabolic process, D-amino acid catabolic process, D-serine catabolic process, dopamine biosynthetic process, D-alanine catabolic process, obsolete D-serine metabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-22.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-22 |

## Associated conditions {#conditions}

[DAO-related disorder](https://sugi.bio/atlas/disease/dao-related-disorder/).

**Reported phenotype names (ClinVar):** DAO-related disorder, DAO-related condition.

## Similar variants {#similar}

Related DAO variant pages (same residue, condition, or type): [DAO p.Pro103Leu](/variant/dao-p-pro103leu), [DAO p.Arg290Gln](/variant/dao-p-arg290gln), [DAO p.Arg297His](/variant/dao-p-arg297his), [DAO p.Arg2Ser](/variant/dao-p-arg2ser), [DAO p.Arg38His](/variant/dao-p-arg38his), [DAO p.Gly131Cys](/variant/dao-p-gly131cys), [DAO p.Thr235Ile](/variant/dao-p-thr235ile), [DAO p.Arg286Cys](/variant/dao-p-arg286cys).

### 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 2634811). 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.*