# NM_015214.3(DDHD2):c.1771C>A (p.Leu591Ile)

https://sugi.bio/variant/ddhd2-p-leu591ile

## Summary

**DDHD2 p.Leu591Ile (c.1771C>A)** is classified **Uncertain significance** in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-20). AlphaMissense: likely benign (0.1512); Ultra-rare (popmax 0.0117%, amr); Associated with hereditary spastic paraplegia 54.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs758122725 · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0117%, amr)

## For patients & families {#patients}

This is a change in the DDHD2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Leu591Ile |
| Coding change (HGVS c.) | c.1771C>A |
| MANE Select transcript | [NM_015214](https://www.ncbi.nlm.nih.gov/nuccore/NM_015214) |
| dbSNP | [rs758122725](https://www.ncbi.nlm.nih.gov/snp/rs758122725/) |
| Variant type | single nucleotide variant |
| Location | chr8:38253007-38253007 (GRCh38) |
| ClinVar | [VCV1479148](https://www.ncbi.nlm.nih.gov/clinvar/variation/1479148/) |

**All HGVS expressions:** `NC_000008.10:g.38110525C>A`, `NC_000008.11:g.38253007C>A`, `NG_033875.1:g.26517C>A`, `NM_001164232.2:c.1771C>A`, `NM_001362911.2:c.1771C>A`, `NM_001362912.2:c.1771C>A`, `NM_001362913.2:c.1681C>A`, `NM_001362914.2:c.1771C>A`, `NM_015214.3:c.1771C>A`, `NR_156416.2:n.1986C>A`, `NR_156417.2:n.1986C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1512)
- REVEL 0.05 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.3 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.088, GERP -0.279, phastCons 1 — weakly conserved position
- CADD: **PHRED 17.63**. 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 0.91** across the covering region of the MANE Select transcript (38,232,995–38,253,580), spanning 20,585 bp. Chi-square p 0.01. 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, Δ0.26 donor gain), 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 **0.0117%** (amr) · FAF95 0.00543% · FAF99 0.00381% · 7/59,992 in the highest group · 8/1,614,040 alleles overall — ultra-rare (popmax 0.0117%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0117% | 8,570 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |

*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}

Residue **591** lies in a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity); the ddhd domain.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-20.

**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 | 2022-02-20 |

## 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.Leu591=](/variant/ddhd2-p-leu591), [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.Arg232Ter](/variant/ddhd2-p-arg232ter), [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).

### 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 1479148). 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.*