# NM_001170700.3(DTHD1):c.1860del (p.Phe620fs)

https://sugi.bio/variant/dthd1-p-phe620fs

## Summary

**DTHD1 p.Phe620fs (c.1860del)** is classified **Uncertain significance** in DTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). Ultra-rare (popmax 0.0333%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1472500022 · 1 submitter · ultra-rare (popmax 0.0333%, mid)

## For patients & families {#patients}

This is a change in the DTHD1 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 | [DTHD1](https://sugi.bio/atlas/gene/DTHD1/) |
| Protein change (HGVS p.) | p.Phe620fs |
| Coding change (HGVS c.) | c.1860del |
| MANE Select transcript | [NM_001170700](https://www.ncbi.nlm.nih.gov/nuccore/NM_001170700) |
| dbSNP | [rs1472500022](https://www.ncbi.nlm.nih.gov/snp/rs1472500022/) |
| Variant type | Deletion |
| Location | chr4:36308255-36308255 (GRCh38) |
| ClinVar | [VCV841261](https://www.ncbi.nlm.nih.gov/clinvar/variation/841261/) |

**All HGVS expressions:** `NC_000004.11:g.36309880del`, `NC_000004.12:g.36308258del`, `NG_032962.1:g.31644del`, `NM_001136536.5:c.990del`, `NM_001170700.3:c.1860del`, `NM_001378435.1:c.927del`, `NR_160267.1:n.2022del`, `NR_165630.1:n.1936del`

## 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 4.675, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.034, pLI 2.15e-18. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0333%** (mid) · FAF95 0.00588% · FAF99 0.00244% · 2/5,998 in the highest group · 2/1,552,250 alleles overall — ultra-rare (popmax 0.0333%, mid).

*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}

**DTHD1** population constraint: LOEUF 1.034, pLI 2.15e-18, missense-Z 0.29944. *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 69.99, 28% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-31.

**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 | 2024-01-31 |

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

## Similar variants {#similar}

Related DTHD1 variant pages (same residue, condition, or type): [DTHD1 p.Phe620Ser](/variant/dthd1-p-phe620ser), [DTHD1 p.Gln834_Ile836del](/variant/dthd1-p-gln834-ile836del), [DTHD1 p.Lys857fs](/variant/dthd1-p-lys857fs), [DTHD1 p.Ser879fs](/variant/dthd1-p-ser879fs), [DTHD1 p.Asn694fs](/variant/dthd1-p-asn694fs), [DTHD1 p.Asp582fs](/variant/dthd1-p-asp582fs), [DTHD1 p.Glu324fs](/variant/dthd1-p-glu324fs), [DTHD1 p.His849fs](/variant/dthd1-p-his849fs).

### 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 841261). 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.*