# NM_015662.3(IFT172):c.4988C>T (p.Pro1663Leu)

https://sugi.bio/variant/ift172-p-pro1663leu

## Summary

**IFT172 p.Pro1663Leu (c.4988C>T)** is classified **Uncertain significance** in IFT172 (ClinVar, Single submitter, 4 submitters; last evaluated 2020-09-16). AlphaMissense: likely benign (0.213); Very rare (popmax 8.48e-05%, nfe); Associated with retinitis pigmentosa 71.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1357445568 · 4 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 8.48e-05%, 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 4 submitters, and is linked to retinitis pigmentosa 71.

*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, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | IFT172 is a diagnostic-grade gene on 17 Genomics England panels |

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

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016101/index) · [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.Pro1663Leu |
| Coding change (HGVS c.) | c.4988C>T |
| MANE Select transcript | [NM_015662](https://www.ncbi.nlm.nih.gov/nuccore/NM_015662) |
| dbSNP | [rs1357445568](https://www.ncbi.nlm.nih.gov/snp/rs1357445568/) |
| Variant type | single nucleotide variant |
| Location | chr2:27445376-27445376 (GRCh38) |
| ClinVar | [VCV1042137](https://www.ncbi.nlm.nih.gov/clinvar/variation/1042137/) |

**All HGVS expressions:** `NC_000002.11:g.27668243G>A`, `NC_000002.12:g.27445376G>A`, `NG_034068.1:g.49436C>T`, `NM_001168364.2:c.*6-925G>A`, `NM_001410739.1:c.4922C>T`, `NM_015662.3:c.4988C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.213)
- REVEL 0.581 (indeterminate)
- SaProt LLR -10.307 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 11.79, GERP 2.12, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.6**. 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 0.89** across the covering region of the MANE Select transcript (27,444,435–27,454,110), spanning 9,675 bp. Chi-square p 0.0028. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **8.48e-05%** (nfe) · 1/1,179,688 in the highest group · 1/1,613,060 alleles overall — very rare (popmax 8.48e-05%, 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 2020-09-16.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2016–2020); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Uncertain significance | no assertion criteria provided | clinical testing | 2016-01-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-09-16 |

## Associated conditions {#conditions}

[retinitis pigmentosa 71](https://sugi.bio/atlas/disease/retinitis-pigmentosa-71/), [short-rib thoracic dysplasia 10 with or without polydactyly](https://sugi.bio/atlas/disease/short-rib-thoracic-dysplasia-10-with-or-without-polydactyly/), [inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa 71, Short-rib thoracic dysplasia 10 with or without polydactyly, not provided, Retinal dystrophy, none provided, Inherited retinal dystrophy.

## Similar variants {#similar}

Related IFT172 variant pages (same residue, condition, or type): [IFT172 c.1411+2T>C](/variant/ift172-c-1411-plus-2t-c), [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.2443-1G>C](/variant/ift172-c-2443-minus-1g-c), [IFT172 c.2976-2A>T](/variant/ift172-c-2976-minus-2a-t), [IFT172 c.3111+1G>T](/variant/ift172-c-3111-plus-1g-t), [IFT172 c.3821+1G>A](/variant/ift172-c-3821-plus-1g-a), [IFT172 c.786-2A>G](/variant/ift172-c-786-minus-2a-g).

### 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 1042137). 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.*