# NM_004859.4(CLTC):c.4989G>A (p.Pro1663=)

https://sugi.bio/variant/cltc-p-pro1663

## Summary

**CLTC p.Pro1663= (c.4989G>A)** is classified **Likely benign** in CLTC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-24). Ultra-rare (popmax 0.033%, sas); Associated with intellectual disability, autosomal dominant 56.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs144269102 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.033%, sas)

## For patients & families {#patients}

This is a change in the CLTC gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to intellectual disability, autosomal dominant 56.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013524/index) · [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.Pro1663= |
| Coding change (HGVS c.) | c.4989G>A |
| MANE Select transcript | [NM_004859](https://www.ncbi.nlm.nih.gov/nuccore/NM_004859) |
| dbSNP | [rs144269102](https://www.ncbi.nlm.nih.gov/snp/rs144269102/) |
| Variant type | single nucleotide variant |
| Location | chr17:59693813-59693813 (GRCh38) |
| ClinVar | [VCV1535158](https://www.ncbi.nlm.nih.gov/clinvar/variation/1535158/) |

**All HGVS expressions:** `NC_000017.10:g.57771174G>A`, `NC_000017.11:g.59693813G>A`, `NG_047043.1:g.79125G>A`, `NM_001288653.2:c.5001G>A`, `NM_004859.4:c.4989G>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 (below), not from a missing predictor score.
- Conservation: phyloP -1.027, GERP -3.59 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 3.879**. 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: **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 **0.033%** (sas) · FAF95 0.0237% · FAF99 0.0205% · 30/91,014 in the highest group · 50/1,613,046 alleles overall — ultra-rare (popmax 0.033%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.033% | 3,034 |
| Admixed American | 0.00334% | 29,948 |
| African / African-American | 0.00267% | 37,403 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,434 |
| European (non-Finnish) | 0.00127% | 78,639 |

*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 **1663** lies in the 'heavy chain arm' region; the 'proximal segment' region; the 'trimerization' region; a UniProt-annotated variant site (in mrd56).

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.Pro1663= falls in the heavy chain arm 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-24.

**Submitter consensus:** conflicting (2 Likely benign, 1 Likely Benign).

**Submission history:** 3 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2025-07-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-24 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-29 |

## Associated conditions {#conditions}

[intellectual disability, autosomal dominant 56](https://sugi.bio/atlas/disease/intellectual-disability-autosomal-dominant-56/).

**Reported phenotype names (ClinVar):** Intellectual disability, autosomal dominant 56, not provided, not specified, AllHighlyPenetrant, MENTAL RETARDATION, AUTOSOMAL DOMINANT 56, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 56, none provided.

## Similar variants {#similar}

Related CLTC variant pages (same residue, condition, or type): [CLTC p.Pro1663Leu](/variant/cltc-p-pro1663leu), [CLTC p.Arg1165Ter](/variant/cltc-p-arg1165ter), [CLTC p.Arg1251Ter](/variant/cltc-p-arg1251ter), [CLTC p.Arg1311Ter](/variant/cltc-p-arg1311ter), [CLTC p.Arg63Ter](/variant/cltc-p-arg63ter), [CLTC p.Pro890Leu](/variant/cltc-p-pro890leu), [CLTC p.Tyr1574Ter](/variant/cltc-p-tyr1574ter), [CLTC c.4605+3T>A](/variant/cltc-c-4605-plus-3t-a).

### 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 1535158). 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.*