# NM_001383.6(DPH1):c.622C>T (p.Pro208Ser)

https://sugi.bio/variant/dph1-p-pro208ser

## Summary

**DPH1 p.Pro208Ser (c.622C>T)** is classified **Uncertain significance** in DPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely benign (0.3037); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the DPH1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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 | [DPH1](https://sugi.bio/atlas/gene/DPH1/) |
| Protein change (HGVS p.) | p.Pro208Ser |
| Coding change (HGVS c.) | c.622C>T |
| MANE Select transcript | [NM_001383](https://www.ncbi.nlm.nih.gov/nuccore/NM_001383) |
| Variant type | single nucleotide variant |
| Location | chr17:2036898-2036898 (GRCh38) |
| ClinVar | [VCV3273586](https://www.ncbi.nlm.nih.gov/clinvar/variation/3273586/) |

**All HGVS expressions:** `NC_000017.10:g.1940192C>T`, `NC_000017.11:g.2036898C>T`, `NG_051946.1:g.11787C>T`, `NM_001346574.1:c.637C>T`, `NM_001346575.1:c.604C>T`, `NM_001346576.2:c.217C>T`, `NM_001383.6:c.622C>T`, `NR_144474.2:n.639C>T`, `NR_144475.2:n.606C>T`, `NR_144476.2:n.639C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3037)
- REVEL 0.306 (indeterminate)
- Conservation: phyloP 7.613, GERP 2.49, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P213S** vs ClinVar **P208S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 25.9**. 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 1.07** across the covering region of the MANE Select transcript (2,030,170–2,041,854), spanning 11,684 bp. Chi-square p 0.074. 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 (C>G, Δ0.25 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 **0.00134%** (afr) · 1/74,896 in the highest group · 1/1,613,724 alleles overall — very rare (popmax 0.00134%, afr).

*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}

**DPH1** population constraint: LOEUF 1.321, pLI 9.9258e-22, missense-Z -0.4356. *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):

- **developmental delay with short stature, dysmorphic facial features, and sparse hair** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.00, 81% of residues very-high.

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

*Describes the biological roles of DPH1 (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}

DPH1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of diphthamide-EEF2](https://reactome.org/content/detail/R-HSA-5358493) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-12.

**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 | 2024-05-12 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related DPH1 variant pages (same residue, condition, or type): [DPH1 p.Arg144Trp](/variant/dph1-p-arg144trp), [DPH1 p.Ile241Phe](/variant/dph1-p-ile241phe), [DPH1 p.Lys38Thr](/variant/dph1-p-lys38thr), [DPH1 c.279-5C>T](/variant/dph1-c-279-minus-5c-t), [DPH1 c.558+4G>C](/variant/dph1-c-558-plus-4g-c), [DPH1 c.-12C>T](/variant/dph1-c-minus-12c-t), [DPH1 c.-2T>A](/variant/dph1-c-minus-2t-a), [DPH1 c.-6C>G](/variant/dph1-c-minus-6c-g).

### 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 3273586). 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.*