# NM_015662.3(IFT172):c.909G>A (p.Val303=)

https://sugi.bio/variant/ift172-p-val303

## Summary

**IFT172 p.Val303= (c.909G>A)** is classified **Uncertain significance** in IFT172 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-13). Very rare (popmax 0.00268%, afr); Associated with retinitis pigmentosa 71.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs139685481 · 2 submitters · 2 linked conditions · very rare (popmax 0.00268%, afr)

## 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 2 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.Val303= |
| Coding change (HGVS c.) | c.909G>A |
| MANE Select transcript | [NM_015662](https://www.ncbi.nlm.nih.gov/nuccore/NM_015662) |
| dbSNP | [rs139685481](https://www.ncbi.nlm.nih.gov/snp/rs139685481/) |
| Variant type | single nucleotide variant |
| Location | chr2:27480026-27480026 (GRCh38) |
| ClinVar | [VCV1356410](https://www.ncbi.nlm.nih.gov/clinvar/variation/1356410/) |

**All HGVS expressions:** `NC_000002.11:g.27702893C>T`, `NC_000002.12:g.27480026C>T`, `NG_034068.1:g.14786G>A`, `NM_015662.2:c.909G>A`, `NM_015662.3:c.909G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.85) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -1.899, GERP -5.05 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 14.39**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.85**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.76** (loss), gain 0.03 / loss 0.76. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00268%** (afr) · FAF95 0.000444% · FAF99 0.000166% · 2/74,740 in the highest group · 3/1,611,984 alleles overall — very rare (popmax 0.00268%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00268% | 37,370 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,378 |

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-13.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-26 |

## 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/).

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

## 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 1356410). 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.*