# NM_015512.5(DNAH1):c.6435A>G (p.Pro2145=)

https://sugi.bio/variant/dnah1-p-pro2145

## Summary

**DNAH1 p.Pro2145= (c.6435A>G)** is classified **Benign/Likely benign** in DNAH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). Rare (popmax 0.304%, afr); Associated with spermatogenic failure 18.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs372202417 · 3 submitters · 2 linked conditions · rare (popmax 0.304%, afr)

## For patients & families {#patients}

This is a change in the DNAH1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to spermatogenic failure 18.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018402/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNAH1](https://sugi.bio/atlas/gene/DNAH1/) |
| Protein change (HGVS p.) | p.Pro2145= |
| Coding change (HGVS c.) | c.6435A>G |
| MANE Select transcript | [NM_015512](https://www.ncbi.nlm.nih.gov/nuccore/NM_015512) |
| dbSNP | [rs372202417](https://www.ncbi.nlm.nih.gov/snp/rs372202417/) |
| Variant type | single nucleotide variant |
| Location | chr3:52370735-52370735 (GRCh38) |
| ClinVar | [VCV544675](https://www.ncbi.nlm.nih.gov/clinvar/variation/544675/) |

**All HGVS expressions:** `NC_000003.11:g.52404751A>G`, `NC_000003.12:g.52370735A>G`, `NG_052911.1:g.59417A>G`, `NM_015512.5:c.6435A>G`

## 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 **acceptor loss** (Δ 0.29) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -4, GERP -3.84 — fast-evolving / accelerated position
- CADD: **PHRED 0.746**. 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 **0.29**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**. Largest is acceptor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.304%** (afr) · FAF95 0.272% · FAF99 0.259% · 228/74,910 in the highest group · 252/1,604,484 alleles overall — rare (popmax 0.304%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.304% | 329 |
| Remaining individuals (not grpmax-eligible) | 0.0273% | 3,658 |
| Admixed American | 0.012% | 8,343 |

*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}

**DNAH1** population constraint: LOEUF 0.759, pLI 5.1879e-73, missense-Z 2.589. *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 18** — Definitive (AR)
- **primary ciliary dyskinesia** — Limited (AR)

## Protein context {#protein}

Residue **2145** lies in a UniProt-annotated variant site (in spgf18).

**2 experimental structure(s)** (PDB): [8I3J](https://www.rcsb.org/structure/8I3J), [8J07](https://www.rcsb.org/structure/8J07).

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-03.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-11-03 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-31 |

## Associated conditions {#conditions}

[spermatogenic failure 18](https://sugi.bio/atlas/disease/spermatogenic-failure-18/), [ciliary dyskinesia, primary, 37](https://sugi.bio/atlas/disease/ciliary-dyskinesia-primary-37/).

**Reported phenotype names (ClinVar):** Spermatogenic failure 18, Ciliary dyskinesia, primary, 37, not provided, not specified, AllHighlyPenetrant, none provided, CILIARY DYSKINESIA, PRIMARY, 37, WITH OR WITHOUT SITUS INVERSUS.

## Similar variants {#similar}

Related DNAH1 variant pages (same residue, condition, or type): [DNAH1 p.Pro2145Ser](/variant/dnah1-p-pro2145ser), [DNAH1 c.1034-2A>G](/variant/dnah1-c-1034-minus-2a-g), [DNAH1 c.10474+1G>A](/variant/dnah1-c-10474-plus-1g-a), [DNAH1 c.10968+2C>T](/variant/dnah1-c-10968-plus-2c-t), [DNAH1 c.5244+1G>A](/variant/dnah1-c-5244-plus-1g-a), [DNAH1 p.Arg1702Ter](/variant/dnah1-p-arg1702ter), [DNAH1 p.Arg2479Ter](/variant/dnah1-p-arg2479ter), [DNAH1 p.Arg2622Ter](/variant/dnah1-p-arg2622ter).

### 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 544675). 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.*