# NM_015662.3(IFT172):c.1352G>C (p.Arg451Pro)

https://sugi.bio/variant/ift172-p-arg451pro

## Summary

**IFT172 p.Arg451Pro (c.1352G>C)** is classified **Uncertain significance** in IFT172 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-10). AlphaMissense: likely benign (0.1968); Very rare (popmax 0.0011%, nfe); Associated with IFT172-related disorder.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs753504432 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0011%, nfe)

## For patients & families {#patients}

This is a change in the IFT172 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to IFT172-related disorder.

*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 | [IFT172](https://sugi.bio/atlas/gene/IFT172/) |
| Protein change (HGVS p.) | p.Arg451Pro |
| Coding change (HGVS c.) | c.1352G>C |
| MANE Select transcript | [NM_015662](https://www.ncbi.nlm.nih.gov/nuccore/NM_015662) |
| dbSNP | [rs753504432](https://www.ncbi.nlm.nih.gov/snp/rs753504432/) |
| Variant type | single nucleotide variant |
| Location | chr2:27476700-27476700 (GRCh38) |
| ClinVar | [VCV2628730](https://www.ncbi.nlm.nih.gov/clinvar/variation/2628730/) |

**All HGVS expressions:** `NC_000002.11:g.27699567C>G`, `NC_000002.12:g.27476700C>G`, `NG_034068.1:g.18112G>C`, `NM_001410739.1:c.1352G>C`, `NM_015662.3:c.1352G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1968)
- REVEL 0.218 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.848 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.228, GERP -4.29, phastCons 0.975 — weakly conserved position
- CADD: **PHRED 18.66**. 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 (27,457,943–27,489,653), spanning 31,710 bp. Chi-square p 0.013. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.27**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.27**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (nfe) · FAF95 0.000615% · FAF99 0.000474% · 13/1,178,752 in the highest group · 13/1,612,596 alleles overall — very rare (popmax 0.0011%, nfe).

*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}

**IFT172** population constraint: LOEUF 0.745, pLI 1.2319e-29, missense-Z 2.704. *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):

- **ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.98, 25% of residues very-high.

**1 experimental structure(s)** (PDB): [9H2D](https://www.rcsb.org/structure/9H2D).

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

*Describes the biological roles of IFT172 (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.*


### Pathways affected {#pathways}

IFT172 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Hedgehog 'off' state](https://reactome.org/content/detail/R-HSA-5610787) | curated |
| [Intraflagellar transport](https://reactome.org/content/detail/R-HSA-5620924) | electronic |

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

**Biological process:** cilium assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-10 |

## Associated conditions {#conditions}

[IFT172-related disorder](https://sugi.bio/atlas/disease/ift172-related-disorder/).

**Reported phenotype names (ClinVar):** IFT172-related disorder, IFT172-related condition, IFT172-related disorders.

## Similar variants {#similar}

Related IFT172 variant pages (same residue, condition, or type): [IFT172 p.Arg451Gln](/variant/ift172-p-arg451gln), [IFT172 c.1525-1G>A](/variant/ift172-c-1525-minus-1g-a), [IFT172 c.184-2A>C](/variant/ift172-c-184-minus-2a-c), [IFT172 c.786-2A>G](/variant/ift172-c-786-minus-2a-g), [IFT172 p.Arg346Ter](/variant/ift172-p-arg346ter), [IFT172 p.Arg38Ter](/variant/ift172-p-arg38ter), [IFT172 p.Arg685Ter](/variant/ift172-p-arg685ter), [IFT172 p.Arg789Ter](/variant/ift172-p-arg789ter).

### 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 2628730). 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.*