# NM_001347886.2(DNAH3):c.7401C>T (p.Asp2467=)

https://sugi.bio/variant/dnah3-p-asp2467

## Summary

**DNAH3 p.Asp2467= (c.7401C>T)** is classified **Likely benign** in DNAH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-01). Rare (popmax 0.525%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs139502385 · 1 submitter · rare (popmax 0.525%, nfe)

## For patients & families {#patients}

This is a change in the DNAH3 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 | [DNAH3](https://sugi.bio/atlas/gene/DNAH3/) |
| Protein change (HGVS p.) | p.Asp2467= |
| Coding change (HGVS c.) | c.7401C>T |
| MANE Select transcript | [NM_001347886](https://www.ncbi.nlm.nih.gov/nuccore/NM_001347886) |
| dbSNP | [rs139502385](https://www.ncbi.nlm.nih.gov/snp/rs139502385/) |
| Variant type | single nucleotide variant |
| Location | chr16:20985203-20985203 (GRCh38) |
| ClinVar | [VCV2646294](https://www.ncbi.nlm.nih.gov/clinvar/variation/2646294/) |

**All HGVS expressions:** `NC_000016.10:g.20985203G>A`, `NC_000016.9:g.20996525G>A`, `NG_052617.1:g.179239C>T`, `NM_001347886.2:c.7401C>T`, `NM_017539.2:c.7539C>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 (below), not from a missing predictor score.
- Conservation: phyloP -5.167, GERP -5.8 — fast-evolving / accelerated position
- CADD: **PHRED 0.059**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.41 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 **0.525%** (nfe) · FAF95 0.514% · FAF99 0.51% · 6,199/1,180,030 in the highest group · 7,156/1,614,100 alleles overall — rare (popmax 0.525%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.525% | 190 |
| Middle Eastern | 0.445% | 225 |
| Remaining individuals (not grpmax-eligible) | 0.389% | 257 |
| South Asian | 0.363% | 275 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.314% | 318 |
| Admixed American | 0.227% | 441 |
| African / African-American | 0.117% | 852 |
| Finnish (not grpmax-eligible) | 0.0593% | 1,685 |
| East Asian | 0.00223% | 44,876 |

*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}

**DNAH3** population constraint: LOEUF 0.834, pLI 5.7231e-77, missense-Z 2.494. *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 **2467** lies in a UniProt-annotated variant site (found in a male with oligoasthenoteratozoospermia; uncertain significance; severely impaired sperm motility; multiple morphological abnormalities of the sperm flagella; partial loss and disintegration of the flagellar axoneme, accompanied by damage to the mitochondrial sheath); a UniProt-annotated variant site (found in a male with asthenoteratozoospermia; uncertain significance; severely impaired sperm motility; multiple morphological abnormalities of the sperm flagella; disorganization of flagellar components, notably inner dynein arms); the 'aaa 4' region.

**1 experimental structure(s)** (PDB): [8J07](https://www.rcsb.org/structure/8J07).

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-05-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-01 |

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

## Similar variants {#similar}

Related DNAH3 variant pages (same residue, condition, or type): [DNAH3 p.Ala1918Gly](/variant/dnah3-p-ala1918gly), [DNAH3 p.Arg1228Gln](/variant/dnah3-p-arg1228gln), [DNAH3 p.Arg635Gln](/variant/dnah3-p-arg635gln), [DNAH3 p.Asn1728Ser](/variant/dnah3-p-asn1728ser), [DNAH3 p.Asp3656Asn](/variant/dnah3-p-asp3656asn), [DNAH3 p.Leu2597Val](/variant/dnah3-p-leu2597val), [DNAH3 p.Leu4044Phe](/variant/dnah3-p-leu4044phe), [DNAH3 p.Lys374Gln](/variant/dnah3-p-lys374gln).

### 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 2646294). 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.*