# NM_015512.5(DNAH1):c.1384C>T (p.Pro462Ser)

https://sugi.bio/variant/dnah1-p-pro462ser

## Summary

**DNAH1 p.Pro462Ser (c.1384C>T)** is classified **Benign/Likely benign** in DNAH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1875); Rare (popmax 0.49%, afr); Associated with spermatogenic failure 18.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs201341419 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.49%, 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 4 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.Pro462Ser |
| Coding change (HGVS c.) | c.1384C>T |
| MANE Select transcript | [NM_015512](https://www.ncbi.nlm.nih.gov/nuccore/NM_015512) |
| dbSNP | [rs201341419](https://www.ncbi.nlm.nih.gov/snp/rs201341419/) |
| Variant type | single nucleotide variant |
| Location | chr3:52344587-52344587 (GRCh38) |
| ClinVar | [VCV772266](https://www.ncbi.nlm.nih.gov/clinvar/variation/772266/) |

**All HGVS expressions:** `NC_000003.11:g.52378603C>T`, `NC_000003.12:g.52344587C>T`, `NG_052911.1:g.33269C>T`, `NM_015512.5:c.1384C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1875)
- REVEL 0.176 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated
- Conservation: phyloP 7.592, GERP 1.51, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.8**. 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 1.04** across the covering region of the MANE Select transcript (52,322,443–52,352,553), spanning 30,110 bp. Chi-square p 0.21. 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 (C>G, Δ0.34 acceptor 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 **0.49%** (afr) · FAF95 0.449% · FAF99 0.433% · 368/75,058 in the highest group · 434/1,613,998 alleles overall — rare (popmax 0.49%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.49% | 204 |
| Remaining individuals (not grpmax-eligible) | 0.0512% | 1,953 |
| Admixed American | 0.0466% | 2,144 |
| Middle Eastern | 0.0165% | 6,058 |
| South Asian | 0.00329% | 30,359 |
| European (non-Finnish) | 0.00017% | 589,943 |

*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 **462** lies in the 'stem' region.

**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 2026-01-05.

**Submitter consensus:** conflicting (3 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-01-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-05 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-08-06 |

## 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, DNAH1-related disorder, not provided, not specified, AllHighlyPenetrant, DNAH1-related condition, 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.Pro462=](/variant/dnah1-p-pro462), [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 772266). 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.*