# NM_004859.4(CLTC):c.469C>A (p.Arg157Ser)

https://sugi.bio/variant/cltc-p-arg157ser

## Summary

**CLTC p.Arg157Ser (c.469C>A)** is classified **Uncertain significance** in CLTC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: likely pathogenic (0.9232); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CLTC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [CLTC](https://sugi.bio/atlas/gene/CLTC/) |
| Protein change (HGVS p.) | p.Arg157Ser |
| Coding change (HGVS c.) | c.469C>A |
| MANE Select transcript | [NM_004859](https://www.ncbi.nlm.nih.gov/nuccore/NM_004859) |
| Variant type | single nucleotide variant |
| Location | chr17:59647616-59647616 (GRCh38) |
| ClinVar | [VCV3493988](https://www.ncbi.nlm.nih.gov/clinvar/variation/3493988/) |

**All HGVS expressions:** `NC_000017.10:g.57724977C>A`, `NC_000017.11:g.59647616C>A`, `NG_047043.1:g.32928C>A`, `NM_001288653.2:c.481C>A`, `NM_004859.4:c.469C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9232)
- REVEL 0.264 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -13.317 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 3.352, GERP 1.9, phastCons 0.998 — highly conserved (agrees)
- CADD: **PHRED 23.8**. 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 0.37** across the covering region of the MANE Select transcript (59,644,310–59,666,878), spanning 22,568 bp. Chi-square p 5.1e-71. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.36 donor gain), 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CLTC** population constraint: LOEUF 0.104, pLI 1, missense-Z 10.229; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **157** lies in the 'wd40-like repeat 4' region; the 'globular terminal domain' region; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 75.62, 8% of residues very-high.

**10 experimental structure(s)** (PDB): [2XZG](https://www.rcsb.org/structure/2XZG), [4G55](https://www.rcsb.org/structure/4G55), [6E4L](https://www.rcsb.org/structure/6E4L), [6QNN](https://www.rcsb.org/structure/6QNN), [6QNP](https://www.rcsb.org/structure/6QNP), [7BN1](https://www.rcsb.org/structure/7BN1).

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

*Describes the biological roles of CLTC (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.*

**How this variant is thought to act:** CLTC's established molecular role includes RNA binding. p.Arg157Ser falls in the wd40-like repeat 4 region. In Reactome, CLTC is annotated in disease pathway(s) including **ALK mutants bind TKIs**, **Entry of Influenza Virion into Host Cell via Endocytosis**.

**Disease mechanism (Reactome):** CLTC loss or alteration is curated in [ALK mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9700645), [Entry of Influenza Virion into Host Cell via Endocytosis](https://reactome.org/content/detail/R-HSA-168275), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370).

### Pathways affected {#pathways}

CLTC participates in **19 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ALK mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9700645) | curated |
| ⚕ [Entry of Influenza Virion into Host Cell via Endocytosis](https://reactome.org/content/detail/R-HSA-168275) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | curated |
| [Formation of annular gap junctions](https://reactome.org/content/detail/R-HSA-196025) | curated |
| [Gap junction degradation](https://reactome.org/content/detail/R-HSA-190873) | curated |
| [LDL clearance](https://reactome.org/content/detail/R-HSA-8964038) | curated |
| [Lysosome Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432720) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [RHOU GTPase cycle](https://reactome.org/content/detail/R-HSA-9013420) | curated |
| [RHOV GTPase cycle](https://reactome.org/content/detail/R-HSA-9013424) | curated |
| [VLDLR internalisation and degradation](https://reactome.org/content/detail/R-HSA-8866427) | curated |
| [WNT5A-dependent internalization of FZD2, FZD5 and ROR2](https://reactome.org/content/detail/R-HSA-5140745) | curated |
| [WNT5A-dependent internalization of FZD4](https://reactome.org/content/detail/R-HSA-5099900) | curated |
| [Golgi Associated Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432722) | other |
| [Recycling pathway of L1](https://reactome.org/content/detail/R-HSA-437239) | electronic |
| [Retrograde neurotrophin signalling](https://reactome.org/content/detail/R-HSA-177504) | electronic |

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

**Molecular function:** RNA binding, double-stranded RNA binding, clathrin light chain binding, low-density lipoprotein particle receptor binding, disordered domain specific binding, ubiquitin-specific protease binding.

**Biological process:** mitotic cell cycle, osteoblast differentiation, receptor-mediated endocytosis, receptor internalization, transferrin transport, retrograde transport, endosome to Golgi.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-05 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CLTC variant pages (same residue, condition, or type): [CLTC p.Arg157Cys](/variant/cltc-p-arg157cys), [CLTC p.Ala1259Thr](/variant/cltc-p-ala1259thr), [CLTC p.Ala198Thr](/variant/cltc-p-ala198thr), [CLTC p.Arg923His](/variant/cltc-p-arg923his), [CLTC p.Arg949His](/variant/cltc-p-arg949his), [CLTC p.Asn1078Ser](/variant/cltc-p-asn1078ser), [CLTC p.Asn1145Ser](/variant/cltc-p-asn1145ser), [CLTC p.Asn340Ser](/variant/cltc-p-asn340ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3493988). 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.*