# NM_015650.4(IFT54):c.1869C>T (p.Ser623=)

https://sugi.bio/variant/ift54-p-ser623

## Summary

**IFT54 p.Ser623= (c.1869C>T)** is classified **Likely benign** in IFT54 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). Very rare (popmax 0.000763%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs201903517 · 2 submitters · very rare (popmax 0.000763%, nfe)

## For patients & families {#patients}

This is a change in the IFT54 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [IFT54](https://sugi.bio/atlas/gene/IFT54/) |
| Protein change (HGVS p.) | p.Ser623= |
| Coding change (HGVS c.) | c.1869C>T |
| MANE Select transcript | [NM_015650](https://www.ncbi.nlm.nih.gov/nuccore/NM_015650) |
| dbSNP | [rs201903517](https://www.ncbi.nlm.nih.gov/snp/rs201903517/) |
| Variant type | single nucleotide variant |
| Location | chr2:238397638-238397638 (GRCh38) |
| ClinVar | [VCV1427024](https://www.ncbi.nlm.nih.gov/clinvar/variation/1427024/) |

**All HGVS expressions:** `NC_000002.11:g.239306279C>T`, `NC_000002.12:g.238397638C>T`, `NG_053055.1:g.82150C>T`, `NM_001139490.1:c.1671C>T`, `NM_015650.4:c.1869C>T`

## 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 gain** (Δ 0.49) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -20, GERP -2.74 — fast-evolving / accelerated position
- CADD: **PHRED 11.03**. 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 **0.02**, acceptor gain **0.00**, donor gain **0.49**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.49**.
- Population frequency (gnomAD v4.1): grpmax **0.000763%** (nfe) · FAF95 0.000359% · FAF99 0.00026% · 9/1,179,216 in the highest group · 11/1,610,412 alleles overall — very rare (popmax 0.000763%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,558 |
| Finnish (not grpmax-eligible) | 0.0016% | 62,410 |
| European (non-Finnish) (grpmax) | 0.000763% | 131,024 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


Curated gene–disease validity (ClinGen):

- **ciliopathy** — Definitive (AR)

## Protein context {#protein}

Residue **623** lies in the 'disc1-interaction domain' region.

AlphaFold model confidence (whole protein): pLDDT 61.95, 32% of residues very-high.

**2 experimental structure(s)** (PDB): [2EQO](https://www.rcsb.org/structure/2EQO), [8KCQ](https://www.rcsb.org/structure/8KCQ).

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

*Describes the biological roles of IFT54 (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}

IFT54 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Intraflagellar transport](https://reactome.org/content/detail/R-HSA-5620924) | electronic |

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

**Biological process:** morphogenesis of a polarized epithelium, kidney development, negative regulation of protein phosphorylation, negative regulation of protein-containing complex assembly, negative regulation of type I interferon production, negative regulation of defense response to virus.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-24.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-24 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-07-22 |

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

## Similar variants {#similar}

Related IFT54 variant pages (same residue, condition, or type): [TRAF3IP1 p.Ser623Arg](/variant/traf3ip1-p-ser623arg), [IFT54 c.1159+1G>C](/variant/ift54-c-1159-plus-1g-c), [IFT54 c.988-1G>A](/variant/ift54-c-988-minus-1g-a), [IFT54 c.988-1G>C](/variant/ift54-c-988-minus-1g-c), [IFT54 p.Arg565Ter](/variant/ift54-p-arg565ter), [IFT54 p.Trp572Ter](/variant/ift54-p-trp572ter), [IFT54 c.1452-5T>G](/variant/ift54-c-1452-minus-5t-g), [IFT54 c.1910+3G>T](/variant/ift54-c-1910-plus-3g-t).

### 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 1427024). 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.*