# NM_015662.3(IFT172):c.1674C>G (p.Val558=)

https://sugi.bio/variant/ift172-p-val558

## Summary

**IFT172 p.Val558= (c.1674C>G)** is classified **Likely benign** in IFT172 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-16). Very rare (popmax 0.00223%, sas); Associated with retinitis pigmentosa 71.

**At a glance:** Likely benign · review: Single submitter · rsID rs1455569315 · 1 submitter · 2 linked conditions · very rare (popmax 0.00223%, sas)

## For patients & families {#patients}

This is a change in the IFT172 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Val558= |
| Coding change (HGVS c.) | c.1674C>G |
| MANE Select transcript | [NM_015662](https://www.ncbi.nlm.nih.gov/nuccore/NM_015662) |
| dbSNP | [rs1455569315](https://www.ncbi.nlm.nih.gov/snp/rs1455569315/) |
| Variant type | single nucleotide variant |
| Location | chr2:27470946-27470946 (GRCh38) |
| ClinVar | [VCV1122814](https://www.ncbi.nlm.nih.gov/clinvar/variation/1122814/) |

**All HGVS expressions:** `NC_000002.11:g.27693813G>C`, `NC_000002.12:g.27470946G>C`, `NG_034068.1:g.23866C>G`, `NM_015662.3:c.1674C>G`

## 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 4.329, GERP -0.507, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 6.44**. 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 (G>T, Δ0.39 donor 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 **0.00223%** (sas) · FAF95 0.00037% · FAF99 0.000139% · 2/89,704 in the highest group · 2/1,606,776 alleles overall — very rare (popmax 0.00223%, sas).

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-16 |

## 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/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa 71, Short-rib thoracic dysplasia 10 with or without polydactyly.

## Same-residue context {#hotspot}

Residue **558** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [IFT172 p.Val558fs](/variant/ift172-p-val558fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related IFT172 variant pages (same residue, condition, or type): [IFT172 p.Val558fs](/variant/ift172-p-val558fs), [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).

### 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 1122814). 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.*