# NM_001160148.2(DDHD1):c.2031C>T (p.Ser677=)

https://sugi.bio/variant/ddhd1-p-ser677

## Summary

**DDHD1 p.Ser677= (c.2031C>T)** is classified **Likely benign** in DDHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-08). Very rare (popmax 0.00153%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs772845212 · 1 submitter · very rare (popmax 0.00153%, nfe)

## For patients & families {#patients}

This is a change in the DDHD1 gene that is classified as likely benign — not considered disease-causing, 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 | [DDHD1](https://sugi.bio/atlas/gene/DDHD1/) |
| Protein change (HGVS p.) | p.Ser677= |
| Coding change (HGVS c.) | c.2031C>T |
| MANE Select transcript | [NM_001160148](https://www.ncbi.nlm.nih.gov/nuccore/NM_001160148) |
| dbSNP | [rs772845212](https://www.ncbi.nlm.nih.gov/snp/rs772845212/) |
| Variant type | single nucleotide variant |
| Location | chr14:53055874-53055874 (GRCh38) |
| ClinVar | [VCV682212](https://www.ncbi.nlm.nih.gov/clinvar/variation/682212/) |

**All HGVS expressions:** `NC_000014.8:g.53522592G>A`, `NC_000014.9:g.53055874G>A`, `NG_042832.1:g.102455C>T`, `NM_001160147.2:c.2052C>T`, `NM_001160148.2:c.2031C>T`, `NM_030637.3:c.2031C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.27) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 8.68, GERP 1.89, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.69**. 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 **0.16**, donor loss **0.01**, acceptor gain **0.27**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.16**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**.
- Pangolin: Δ**0.23** (gain), gain 0.23 / loss 0.13. 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 **0.00153%** (nfe) · FAF95 0.000954% · FAF99 0.000787% · 18/1,179,588 in the highest group · 18/1,613,290 alleles overall — very rare (popmax 0.00153%, nfe).

*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}

**DDHD1** population constraint: LOEUF 0.642, pLI 4.5078e-05, missense-Z 0.71714; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **hereditary spastic paraplegia** — Definitive (AR)

## Protein context {#protein}

Residue **677** lies in the ddhd domain.

AlphaFold model confidence (whole protein): pLDDT 67.11, 32% of residues very-high.

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

*Describes the biological roles of DDHD1 (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}

DDHD1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PA](https://reactome.org/content/detail/R-HSA-1483166) | curated |

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

**Biological process:** positive regulation of mitochondrial fission.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-05-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-05-08 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related DDHD1 variant pages (same residue, condition, or type): [DDHD1 p.Ala193Val](/variant/ddhd1-p-ala193val), [DDHD1 p.Ala94Pro](/variant/ddhd1-p-ala94pro), [DDHD1 p.Arg204Trp](/variant/ddhd1-p-arg204trp), [DDHD1 p.Arg288His](/variant/ddhd1-p-arg288his), [DDHD1 p.Arg554Gln](/variant/ddhd1-p-arg554gln), [DDHD1 p.Arg570Gln](/variant/ddhd1-p-arg570gln), [DDHD1 p.Arg588Gln](/variant/ddhd1-p-arg588gln), [DDHD1 p.Arg596Gln](/variant/ddhd1-p-arg596gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 682212). 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.*