# NM_015214.3(DDHD2):c.694C>T (p.Arg232Ter)

https://sugi.bio/variant/ddhd2-p-arg232ter

## Summary

**DDHD2 p.Arg232Ter (c.694C>T)** is classified **Pathogenic** in DDHD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-28). Very rare (popmax 0.0011%, sas); Associated with hereditary spastic paraplegia 54.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1249841130 · 2 submitters · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the DDHD2 gene that is considered disease-causing, submitted by 2 submitters, and is linked to hereditary spastic paraplegia 54.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Diagnostic panels | DDHD2 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Autosomal recessive spastic paraplegia type 54** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Spastic paraplegia — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Strabismus — Frequent (79-30%)
- Dysarthria — Frequent (79-30%)
- Gait disturbance — Frequent (79-30%)
- Dysphagia — Frequent (79-30%)
- Spastic gait — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017475/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DDHD2](https://sugi.bio/atlas/gene/DDHD2/) |
| Protein change (HGVS p.) | p.Arg232Ter |
| Coding change (HGVS c.) | c.694C>T |
| MANE Select transcript | [NM_015214](https://www.ncbi.nlm.nih.gov/nuccore/NM_015214) |
| dbSNP | [rs1249841130](https://www.ncbi.nlm.nih.gov/snp/rs1249841130/) |
| Variant type | single nucleotide variant |
| Location | chr8:38240346-38240346 (GRCh38) |
| ClinVar | [VCV634496](https://www.ncbi.nlm.nih.gov/clinvar/variation/634496/) |

**All HGVS expressions:** `NC_000008.10:g.38097864C>T`, `NC_000008.11:g.38240346C>T`, `NG_033875.1:g.13856C>T`, `NM_001164232.2:c.694C>T`, `NM_001362911.2:c.694C>T`, `NM_001362912.2:c.694C>T`, `NM_001362913.2:c.623-1904C>T`, `NM_001362914.2:c.694C>T`, `NM_015214.3:c.694C>T`, `NR_156416.2:n.977C>T`, `NR_156417.2:n.977C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 2.606, GERP -0.078, phastCons 0.996 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.758, pLI 1.2846e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 18**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 38.0**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Pangolin: Δ**0.30** (loss), gain 0.00 / loss 0.30. Not in the SpliceAI release. 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 **0.0011%** (sas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/90,672 in the highest group · 5/1,609,714 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00157% | 63,890 |
| South Asian (grpmax) | 0.0011% | 90,672 |
| European (non-Finnish) | 0.000255% | 392,269 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**DDHD2** population constraint: LOEUF 0.758, pLI 1.2846e-06, missense-Z 1.7398. *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 74.70, 36% of residues very-high.

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

*Describes the biological roles of DDHD2 (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}

DDHD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-08-28.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2019–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2019-01-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-28 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 54](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-54/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 54, Spastic paraplegia 54, autosomal recessive.

## Similar variants {#similar}

Related DDHD2 variant pages (same residue, condition, or type): [DDHD2 p.Arg232Gln](/variant/ddhd2-p-arg232gln), [DDHD2 c.1126-2A>G](/variant/ddhd2-c-1126-minus-2a-g), [DDHD2 c.1248+2T>C](/variant/ddhd2-c-1248-plus-2t-c), [DDHD2 p.Arg329Ter](/variant/ddhd2-p-arg329ter), [DDHD2 p.Arg516Ter](/variant/ddhd2-p-arg516ter), [DDHD2 p.Asp660His](/variant/ddhd2-p-asp660his), [DDHD2 p.Gln286Ter](/variant/ddhd2-p-gln286ter), [DDHD2 p.Trp115Ter](/variant/ddhd2-p-trp115ter).

### 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 634496). 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.*