# NM_024589.3(ROGDI):c.249C>T (p.Ser83=)

https://sugi.bio/variant/rogdi-p-ser83

## Summary

**ROGDI p.Ser83= (c.249C>T)** is classified **Likely benign** in ROGDI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). Very rare (popmax 0.00673%, amr); Associated with amelocerebrohypohidrotic syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs769659198 · 1 submitter · 1 linked condition · very rare (popmax 0.00673%, amr)

## For patients & families {#patients}

This is a change in the ROGDI gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to amelocerebrohypohidrotic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003128/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ROGDI](https://sugi.bio/atlas/gene/ROGDI/) |
| Protein change (HGVS p.) | p.Ser83= |
| Coding change (HGVS c.) | c.249C>T |
| MANE Select transcript | [NM_024589](https://www.ncbi.nlm.nih.gov/nuccore/NM_024589) |
| dbSNP | [rs769659198](https://www.ncbi.nlm.nih.gov/snp/rs769659198/) |
| Variant type | single nucleotide variant |
| Location | chr16:4801273-4801273 (GRCh38) |
| ClinVar | [VCV1620934](https://www.ncbi.nlm.nih.gov/clinvar/variation/1620934/) |

**All HGVS expressions:** `LRG_455:g.6678C>T`, `NC_000016.10:g.4801273G>A`, `NC_000016.9:g.4851274G>A`, `NG_032174.1:g.6678C>T`, `NM_024589.3:c.249C>T`

## 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 8.477, GERP 1.04, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.79**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.29 acceptor 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 **0.00673%** (amr) · FAF95 0.00227% · FAF99 0.00136% · 4/59,454 in the highest group · 4/1,606,618 alleles overall — very rare (popmax 0.00673%, amr).

*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}

**ROGDI** population constraint: LOEUF 1.648, pLI 1.2141e-19, missense-Z -3.6418. *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):

- **amelocerebrohypohidrotic syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **83** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 89.59, 73% of residues very-high.

**2 experimental structure(s)** (PDB): [5XQH](https://www.rcsb.org/structure/5XQH), [5XQI](https://www.rcsb.org/structure/5XQI).

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-08.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-08 |

## Associated conditions {#conditions}

[amelocerebrohypohidrotic syndrome](https://sugi.bio/atlas/disease/amelocerebrohypohidrotic-syndrome/).

**Reported phenotype names (ClinVar):** Amelocerebrohypohidrotic syndrome, EPILEPSY AND YELLOW TEETH, EPILEPSY, DEMENTIA, AND AMELOGENESIS IMPERFECTA, KOHLSCHUTTER SYNDROME, Kohlschutter's syndrome.

## Similar variants {#similar}

Related ROGDI variant pages (same residue, condition, or type): [ROGDI c.117+1G>A](/variant/rogdi-c-117-plus-1g-a), [ROGDI c.46-2A>G](/variant/rogdi-c-46-minus-2a-g), [ROGDI c.531+5G>C](/variant/rogdi-c-531-plus-5g-c), [ROGDI c.645+2T>A](/variant/rogdi-c-645-plus-2t-a), [ROGDI p.Arg157Ter](/variant/rogdi-p-arg157ter), [ROGDI p.Gln112Ter](/variant/rogdi-p-gln112ter), [ROGDI p.Gln114Ter](/variant/rogdi-p-gln114ter), [ROGDI p.Gln96Ter](/variant/rogdi-p-gln96ter).

### 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 1620934). 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.*