# NM_003611.3(OFD1):c.2052C>T (p.Ser684=)

https://sugi.bio/variant/ofd1-p-ser684

## Summary

**OFD1 p.Ser684= (c.2052C>T)** is classified **Benign** in OFD1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). Low-frequency (popmax 3.4%, afr); Associated with Joubert syndrome.

**At a glance:** Benign · review: Multiple submitters · rsID rs61742891 · 9 submitters · 3 linked conditions · low-frequency (popmax 3.4%, afr)

## For patients & families {#patients}

This is a change in the OFD1 gene that is classified as benign — not considered disease-causing, submitted by 9 submitters, and is linked to Joubert syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006802/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.Ser684= |
| Coding change (HGVS c.) | c.2052C>T |
| MANE Select transcript | [NM_003611](https://www.ncbi.nlm.nih.gov/nuccore/NM_003611) |
| dbSNP | [rs61742891](https://www.ncbi.nlm.nih.gov/snp/rs61742891/) |
| Variant type | single nucleotide variant |
| Location | chrX:13760512-13760512 (GRCh38) |
| ClinVar | [VCV159468](https://www.ncbi.nlm.nih.gov/clinvar/variation/159468/) |

**All HGVS expressions:** `NC_000023.10:g.13778631C>T`, `NC_000023.11:g.13760512C>T`, `NG_008872.1:g.30800C>T`, `NM_001330209.2:c.1932C>T`, `NM_001330210.2:c.1632C>T`, `NM_003611.3:c.2052C>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 -5.65, GERP -6.04 — fast-evolving / accelerated position
- CADD: **PHRED 0.07**. 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 (C>G, Δ0.20 acceptor loss), 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 **3.4%** (afr) · FAF95 3.28% · FAF99 3.22% · 1,881/55,254 in the highest group · 2,154/1,167,500 alleles overall — low-frequency (popmax 3.4%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.4% | 29 |
| Admixed American | 0.305% | 328 |
| Middle Eastern | 0.268% | 373 |
| Remaining individuals (not grpmax-eligible) | 0.261% | 383 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0105% | 9,540 |
| European (non-Finnish) | 0.00262% | 38,108 |
| South Asian | 0.00202% | 49,584 |

*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}

Residue **684** lies in the 'mediates the interaction with sdccag8' region.

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. p.Ser684= falls in the mediates the interaction with sdccag8 region.


### 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (8 Benign, 1 Likely benign).

**Submission history:** 9 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2014-12-15 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2021-03-19 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2024-10-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-22 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-01-18 |

## Associated conditions {#conditions}

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

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

## 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 2026-10-06); 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 2026-10-14); 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 159468). 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.*