# NM_003611.3(OFD1):c.1467C>T (p.Ala489=)

https://sugi.bio/variant/ofd1-p-ala489

## Summary

**OFD1 p.Ala489= (c.1467C>T)** is classified **Likely benign** in OFD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-21). Very rare (popmax 0.0053%, afr); Associated with primary ciliary dyskinesia.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1366105128 · 3 submitters · 3 linked conditions · very rare (popmax 0.0053%, afr)

## For patients & families {#patients}

This is a change in the OFD1 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to primary ciliary dyskinesia.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Neonatal |
| Prevalence | 1-5 / 10 000 (Pakistan) |
| Clinical trials | 76 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | OFD1 is a diagnostic-grade gene on 22 Genomics England panels |

**Commonly reported features of Primary ciliary dyskinesia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Chronic otitis media — Frequent (79-30%)
- Recurrent otitis media — Frequent (79-30%)
- Nasal congestion — Frequent (79-30%)
- Chronic rhinitis — Frequent (79-30%)
- Neonatal respiratory distress — Frequent (79-30%)
- Male infertility — Frequent (79-30%)
- Recurrent sinopulmonary infections — Frequent (79-30%)
- Chronic sinusitis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004484/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [OFD1](https://sugi.bio/atlas/gene/OFD1/) |
| Protein change (HGVS p.) | p.Ala489= |
| Coding change (HGVS c.) | c.1467C>T |
| MANE Select transcript | [NM_003611](https://www.ncbi.nlm.nih.gov/nuccore/NM_003611) |
| dbSNP | [rs1366105128](https://www.ncbi.nlm.nih.gov/snp/rs1366105128/) |
| Variant type | single nucleotide variant |
| Location | chrX:13757715-13757715 (GRCh38) |
| ClinVar | [VCV2926953](https://www.ncbi.nlm.nih.gov/clinvar/variation/2926953/) |

**All HGVS expressions:** `NC_000023.10:g.13775834C>T`, `NC_000023.11:g.13757715C>T`, `NG_008872.1:g.28003C>T`, `NG_008872.2:g.48212C>T`, `NM_001330209.2:c.1347C>T`, `NM_001330210.2:c.1047C>T`, `NM_003611.2:c.1467C>T`, `NM_003611.3:c.1467C>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 0.091, GERP -0.67, phastCons 0.067 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.499**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0053%** (afr) · FAF95 0.00141% · FAF99 0.000857% · 3/56,597 in the highest group · 25/1,207,801 alleles overall — very rare (popmax 0.0053%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00651% | 15,370 |
| African / African-American (grpmax) | 0.0053% | 18,866 |
| Admixed American | 0.0022% | 45,522 |
| Remaining individuals (not grpmax-eligible) | 0.0021% | 47,563 |
| European (non-Finnish) | 0.00179% | 55,907 |
| South Asian | 0.00176% | 56,719 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**OFD1** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **OFD1-related ciliopathy** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.41, 32% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of OFD1 (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.*

**How this variant is thought to act:** OFD1's established molecular role includes identical protein binding.


### Pathways affected {#pathways}

OFD1 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Hedgehog 'off' state](https://reactome.org/content/detail/R-HSA-5610787) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding, molecular adaptor activity.

**Biological process:** cilium assembly.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-21.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2023–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-29 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-21 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-21 |

## Associated conditions {#conditions}

[primary ciliary dyskinesia](https://sugi.bio/atlas/disease/primary-ciliary-dyskinesia/), [orofaciodigital syndrome I](https://sugi.bio/atlas/disease/orofaciodigital-syndrome-i/), [Joubert syndrome](https://sugi.bio/atlas/disease/joubert-syndrome/).

**Reported phenotype names (ClinVar):** Primary ciliary dyskinesia, Joubert syndrome, Orofaciodigital syndrome I, not specified, Ciliary dyskinesia, Familial aplasia of the vermis, JOUBERT-BOLTSHAUSER SYNDROME, Papillon-Leage and Psaume Syndrome, Oral-Facial-Digital Syndrome Type I, OFDS I.

## Similar variants {#similar}

Related OFD1 variant pages (same residue, condition, or type): [OFD1 c.1411+1G>A](/variant/ofd1-c-1411-plus-1g-a), [OFD1 c.2600-1G>C](/variant/ofd1-c-2600-minus-1g-c), [OFD1 p.Arg367Ter](/variant/ofd1-p-arg367ter), [OFD1 p.Arg41Ter](/variant/ofd1-p-arg41ter), [OFD1 p.Arg890Ter](/variant/ofd1-p-arg890ter), [OFD1 p.Arg909Ter](/variant/ofd1-p-arg909ter), [OFD1 p.Tyr87Cys](/variant/ofd1-p-tyr87cys), [OFD1 c.2388-3T>C](/variant/ofd1-c-2388-minus-3t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2926953). 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.*