# NM_015214.3(DDHD2):c.1323C>T (p.Phe441=)

https://sugi.bio/variant/ddhd2-p-phe441

## Summary

**DDHD2 p.Phe441= (c.1323C>T)** is classified **Likely benign** in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-19). Very rare (popmax 8.49e-05%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs1183950102 · 1 submitter · very rare (popmax 8.49e-05%, nfe)

## For patients & families {#patients}

This is a change in the DDHD2 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 | [DDHD2](https://sugi.bio/atlas/gene/DDHD2/) |
| Protein change (HGVS p.) | p.Phe441= |
| Coding change (HGVS c.) | c.1323C>T |
| MANE Select transcript | [NM_015214](https://www.ncbi.nlm.nih.gov/nuccore/NM_015214) |
| dbSNP | [rs1183950102](https://www.ncbi.nlm.nih.gov/snp/rs1183950102/) |
| Variant type | single nucleotide variant |
| Location | chr8:38249782-38249782 (GRCh38) |
| ClinVar | [VCV750435](https://www.ncbi.nlm.nih.gov/clinvar/variation/750435/) |

**All HGVS expressions:** `NC_000008.10:g.38107300C>T`, `NC_000008.11:g.38249782C>T`, `NG_033875.1:g.23292C>T`, `NM_001164232.2:c.1323C>T`, `NM_001362911.2:c.1323C>T`, `NM_001362912.2:c.1323C>T`, `NM_001362913.2:c.1233C>T`, `NM_001362914.2:c.1323C>T`, `NM_015214.3:c.1323C>T`, `NR_156416.2:n.1538C>T`, `NR_156417.2:n.1538C>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 **donor loss** (Δ 0.34) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.166, GERP -4.53, phastCons 0.978 — weakly conserved position
- CADD: **PHRED 9.909**. 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 **0.00**, donor loss **0.34**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.34**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.38** (loss), gain 0.00 / loss 0.38. 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 **8.49e-05%** (nfe) · 1/1,177,480 in the highest group · 1/1,458,400 alleles overall — very rare (popmax 8.49e-05%, 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}

**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 **441** lies in a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity); the sam 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-06-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-06-19 |

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

## Similar variants {#similar}

Related DDHD2 variant pages (same residue, condition, or type): [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.Arg422Ter](/variant/ddhd2-p-arg422ter), [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 2026-10-14); 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 750435). 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.*