# NM_003611.3(OFD1):c.274T>C (p.Ser92Pro)

https://sugi.bio/variant/ofd1-p-ser92pro

## Summary

**OFD1 p.Ser92Pro (c.274T>C)** is classified **Likely pathogenic** in OFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-09). AlphaMissense: likely pathogenic (0.8952); Absent from gnomAD v4.1.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the OFD1 gene that is considered likely 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 | [OFD1](https://sugi.bio/atlas/gene/OFD1/) |
| Protein change (HGVS p.) | p.Ser92Pro |
| Coding change (HGVS c.) | c.274T>C |
| MANE Select transcript | [NM_003611](https://www.ncbi.nlm.nih.gov/nuccore/NM_003611) |
| Variant type | single nucleotide variant |
| Location | chrX:13736640-13736640 (GRCh38) |
| ClinVar | [VCV3338817](https://www.ncbi.nlm.nih.gov/clinvar/variation/3338817/) |

**All HGVS expressions:** `NC_000023.10:g.13754759T>C`, `NC_000023.11:g.13736640T>C`, `NG_008872.1:g.6928T>C`, `NG_011555.1:g.2984A>G`, `NM_001330209.2:c.274T>C`, `NM_001330210.2:c.-272T>C`, `NM_003611.3:c.274T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8952) — concordant with the pathogenic call
- REVEL 0.975 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.694 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.30) — consistent with the pathogenic call
- Conservation: phyloP 7.796, GERP 2.4, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in OFD1 (of 5,970 modeled).
- CADD: **PHRED 27.3**. 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 0.93** across the covering region of the MANE Select transcript (13,735,072–13,760,339), spanning 25,267 bp. Chi-square p 0.12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.02**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.02**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **92** lies in the lish domain.

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.Ser92Pro falls in the lish domain.


### 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 pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-09.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-09-09 |

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

## Similar variants {#similar}

Related OFD1 variant pages (same residue, condition, or type): [OFD1 p.Ser92=](/variant/ofd1-p-ser92), [OFD1 p.Ser92Phe](/variant/ofd1-p-ser92phe), [TRAPPC2 p.Glu92Asp](/variant/trappc2-p-glu92asp), [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 c.655-8A>G](/variant/ofd1-c-655-minus-8a-g), [OFD1 p.Arg367Ter](/variant/ofd1-p-arg367ter), [OFD1 p.Arg41Ter](/variant/ofd1-p-arg41ter).

### 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 3338817). 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.*