# NM_001366028.2(DNAH12):c.5477A>T (p.Asp1826Val)

https://sugi.bio/variant/dnah12-p-asp1826val

## Summary

**DNAH12 p.Asp1826Val (c.5477A>T)** is classified **Uncertain significance** in DNAH12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.1001); Very rare (popmax 0.00274%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1001394819 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00274%, afr)

## For patients & families {#patients}

This is a change in the DNAH12 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [DNAH12](https://sugi.bio/atlas/gene/DNAH12/) |
| Protein change (HGVS p.) | p.Asp1826Val |
| Coding change (HGVS c.) | c.5477A>T |
| MANE Select transcript | [NM_001366028](https://www.ncbi.nlm.nih.gov/nuccore/NM_001366028) |
| dbSNP | [rs1001394819](https://www.ncbi.nlm.nih.gov/snp/rs1001394819/) |
| Variant type | single nucleotide variant |
| Location | chr3:57421603-57421603 (GRCh38) |
| ClinVar | [VCV3083567](https://www.ncbi.nlm.nih.gov/clinvar/variation/3083567/) |

**All HGVS expressions:** `NC_000003.11:g.57407330T>A`, `NC_000003.12:g.57421603T>A`, `NM_001366028.2:c.5477A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1001)
- REVEL 0.09 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 0.175, GERP -3.51 — weakly conserved position
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **D1807V** vs ClinVar **D1826V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 16.19**. 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 1.01** across the covering region of the MANE Select transcript (57,293,784–57,452,931), spanning 159,147 bp. Chi-square p 0.54. 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 (T>C, Δ0.30 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 **0.00274%** (afr) · FAF95 0.000454% · FAF99 0.00017% · 2/73,048 in the highest group · 3/1,551,574 alleles overall — very rare (popmax 0.00274%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00274% | 36,524 |
| European (non-Finnish) | 8.72e-05% | 1,146,990 |

*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}

**DNAH12** population constraint: LOEUF 0.827, pLI 9.1992e-63, missense-Z 1.2387. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **spermatogenic failure** — Definitive (AR)

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-30.

**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 | 2024-01-30 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DNAH12 variant pages (same residue, condition, or type): [DNAH12 c.1650+6G>A](/variant/dnah12-c-1650-plus-6g-a), [DNAH12 c.1912-8A>G](/variant/dnah12-c-1912-minus-8a-g), [DNAH12 c.3053+9A>G](/variant/dnah12-c-3053-plus-9a-g), [DNAH12 c.5253+263A>T](/variant/dnah12-c-5253-plus-263a-t), [DNAH12 c.5253+289C>T](/variant/dnah12-c-5253-plus-289c-t), [DNAH12 c.6948+922=](/variant/dnah12-c-6948-plus-922), [DNAH12 p.Asp1572Asn](/variant/dnah12-p-asp1572asn), [DNAH12 p.Asp224Glu](/variant/dnah12-p-asp224glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3083567). 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.*