# NM_016824.5(ADD3):c.1162G>C (p.Ala388Pro)

https://sugi.bio/variant/add3-p-ala388pro

## Summary

**ADD3 p.Ala388Pro (c.1162G>C)** is classified **Uncertain significance** in ADD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). AlphaMissense: likely benign (0.241); Very rare (popmax 0.00933%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs529703729 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00933%, afr)

## For patients & families {#patients}

This is a change in the ADD3 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 | [ADD3](https://sugi.bio/atlas/gene/ADD3/) |
| Protein change (HGVS p.) | p.Ala388Pro |
| Coding change (HGVS c.) | c.1162G>C |
| MANE Select transcript | [NM_016824](https://www.ncbi.nlm.nih.gov/nuccore/NM_016824) |
| dbSNP | [rs529703729](https://www.ncbi.nlm.nih.gov/snp/rs529703729/) |
| Variant type | single nucleotide variant |
| Location | chr10:110124035-110124035 (GRCh38) |
| ClinVar | [VCV1980197](https://www.ncbi.nlm.nih.gov/clinvar/variation/1980197/) |

**All HGVS expressions:** `NC_000010.10:g.111883793G>C`, `NC_000010.11:g.110124035G>C`, `NG_051033.1:g.132686G>C`, `NM_001121.4:c.1162G>C`, `NM_001320591.2:c.1162G>C`, `NM_001320592.2:c.1162G>C`, `NM_001320593.2:c.1162G>C`, `NM_001320594.2:c.928G>C`, `NM_016824.5:c.1162G>C`, `NM_019903.5:c.1162G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.241)
- REVEL 0.104 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.696 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.744, GERP 1.37, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.4**. 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 0.98** across the covering region of the MANE Select transcript (110,100,654–110,133,615), spanning 32,961 bp. Chi-square p 0.53. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Pangolin: Δ**0.30** (gain), gain 0.30 / loss 0.10. 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 **0.00933%** (afr) · FAF95 0.00437% · FAF99 0.00308% · 7/75,062 in the highest group · 11/1,461,830 alleles overall — very rare (popmax 0.00933%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00933% | 10,723 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,628 |

*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}

**ADD3** population constraint: LOEUF 0.395, pLI 0.99998, missense-Z 0.99475. *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):

- **complex neurodevelopmental disorder with motor features** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 66.83, 23% of residues very-high.

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

*Describes the biological roles of ADD3 (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.*


### Pathways affected {#pathways}

ADD3 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Miscellaneous transport and binding events](https://reactome.org/content/detail/R-HSA-5223345) | curated |
| [RHOD GTPase cycle](https://reactome.org/content/detail/R-HSA-9013405) | curated |
| [RHOF GTPase cycle](https://reactome.org/content/detail/R-HSA-9035034) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-07.

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

### Submitter classifications {#submitters}

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

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

## Similar variants {#similar}

Related ADD3 variant pages (same residue, condition, or type): [ADD3 p.Gly367Asp](/variant/add3-p-gly367asp), [ADD3 c.1733-1G>A](/variant/add3-c-1733-minus-1g-a), [ADD3 p.Ala588Gly](/variant/add3-p-ala588gly), [ADD3 p.Arg27Cys](/variant/add3-p-arg27cys), [ADD3 p.Arg46Gln](/variant/add3-p-arg46gln), [ADD3 p.Arg571His](/variant/add3-p-arg571his), [ADD3 p.Arg645Gln](/variant/add3-p-arg645gln), [ADD3 p.Asn312Asp](/variant/add3-p-asn312asp).

### 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 1980197). 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.*