# NM_015214.3(DDHD2):c.725G>A (p.Arg242His)

https://sugi.bio/variant/ddhd2-p-arg242his

## Summary

**DDHD2 p.Arg242His (c.725G>A)** is classified **Conflicting classifications of pathogenicity** in DDHD2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-08-26). AlphaMissense: likely pathogenic (0.9017); Very rare (popmax 0.004%, amr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs767497993 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.004%, amr)

## For patients & families {#patients}

This is a change in the DDHD2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, 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 | [DDHD2](https://sugi.bio/atlas/gene/DDHD2/) |
| Protein change (HGVS p.) | p.Arg242His |
| Coding change (HGVS c.) | c.725G>A |
| MANE Select transcript | [NM_015214](https://www.ncbi.nlm.nih.gov/nuccore/NM_015214) |
| dbSNP | [rs767497993](https://www.ncbi.nlm.nih.gov/snp/rs767497993/) |
| Variant type | single nucleotide variant |
| Location | chr8:38242262-38242262 (GRCh38) |
| ClinVar | [VCV540290](https://www.ncbi.nlm.nih.gov/clinvar/variation/540290/) |

**All HGVS expressions:** `NC_000008.10:g.38099780G>A`, `NC_000008.11:g.38242262G>A`, `NG_033875.1:g.15772G>A`, `NM_001164232.2:c.725G>A`, `NM_001362911.2:c.725G>A`, `NM_001362912.2:c.725G>A`, `NM_001362913.2:c.635G>A`, `NM_001362914.2:c.725G>A`, `NM_015214.3:c.725G>A`, `NR_156416.2:n.1008G>A`, `NR_156417.2:n.1008G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9017)
- REVEL 0.505 (indeterminate)
- SaProt LLR -13.755 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.45) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 11.67, GERP 0.905, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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.*
- 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 deltas (raw): acceptor loss **0.10**, donor loss **0.00**, acceptor gain **0.45**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.45**, donor gain **0.00**.
- Pangolin: Δ**0.42** (gain), gain 0.42 / loss 0.31. 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 **0.004%** (amr) · FAF95 0.00268% · FAF99 0.00238% · 2/49,968 in the highest group · 48/1,585,198 alleles overall — very rare (popmax 0.004%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00488% | 20,478 |
| Admixed American (grpmax) | 0.004% | 24,984 |
| European (non-Finnish) | 0.00359% | 27,893 |
| African / African-American | 0.00137% | 72,906 |

Remaining individuals 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-08-26.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Pathogenic).

**Submission history:** 4 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Paris Brain Institute, Inserm - ICM | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-14 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-26 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-18 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [hereditary spastic paraplegia 54](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-54/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Hereditary spastic paraplegia 54, not provided, none provided, Spastic paraplegia 54, autosomal recessive.

## Similar variants {#similar}

Related DDHD2 variant pages (same residue, condition, or type): [DDHD2 p.Arg242Cys](/variant/ddhd2-p-arg242cys), [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 540290). 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.*