# NM_015214.3(DDHD2):c.1028G>C (p.Gly343Ala)

https://sugi.bio/variant/ddhd2-p-gly343ala

## Summary

**DDHD2 p.Gly343Ala (c.1028G>C)** is classified **Uncertain significance** in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-28). AlphaMissense: likely pathogenic (0.6914); Very rare (popmax 0.00475%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs760303461 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00475%, nfe)

## 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 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.Gly343Ala |
| Coding change (HGVS c.) | c.1028G>C |
| MANE Select transcript | [NM_015214](https://www.ncbi.nlm.nih.gov/nuccore/NM_015214) |
| dbSNP | [rs760303461](https://www.ncbi.nlm.nih.gov/snp/rs760303461/) |
| Variant type | single nucleotide variant |
| Location | chr8:38245921-38245921 (GRCh38) |
| ClinVar | [VCV2230314](https://www.ncbi.nlm.nih.gov/clinvar/variation/2230314/) |

**All HGVS expressions:** `NC_000008.10:g.38103439G>C`, `NC_000008.11:g.38245921G>C`, `NG_033875.1:g.19431G>C`, `NG_033875.2:g.19338G>C`, `NM_001164232.2:c.1028G>C`, `NM_001362911.2:c.1028G>C`, `NM_001362912.2:c.1028G>C`, `NM_001362913.2:c.938G>C`, `NM_001362914.2:c.1028G>C`, `NM_015214.3:c.1028G>C`, `NR_156416.2:n.1311G>C`, `NR_156417.2:n.1311G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6914)
- REVEL 0.736 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.279 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.82, GERP 1.84, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.0**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.96 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 **0.00475%** (nfe) · FAF95 0.00375% · FAF99 0.00337% · 56/1,180,014 in the highest group · 57/1,613,886 alleles overall — very rare (popmax 0.00475%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00475% | 21,072 |
| African / African-American | 0.00133% | 75,040 |

*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 **343** lies in a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity).

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 2022-04-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-28 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related DDHD2 variant pages (same residue, condition, or type): [DDHD2 p.Asp660His](/variant/ddhd2-p-asp660his), [DDHD2 p.Arg232Gln](/variant/ddhd2-p-arg232gln), [DDHD2 p.Arg329Gln](/variant/ddhd2-p-arg329gln), [DDHD2 p.Arg494Gln](/variant/ddhd2-p-arg494gln), [DDHD2 p.Arg494Trp](/variant/ddhd2-p-arg494trp), [DDHD2 p.Arg595Gln](/variant/ddhd2-p-arg595gln), [DDHD2 p.Arg595Trp](/variant/ddhd2-p-arg595trp), [DDHD2 p.Gly449Cys](/variant/ddhd2-p-gly449cys).

### 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 2026-10-14); 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 2230314). 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.*