# NM_000420.3(KEL):c.140G>C (p.Arg47Pro)

https://sugi.bio/variant/kel-p-arg47pro

## Summary

**KEL p.Arg47Pro (c.140G>C)** is classified **Uncertain significance** in KEL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.1873); Ultra-rare (popmax 0.0345%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs370130119 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0345%, mid)

## For patients & families {#patients}

This is a change in the KEL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [KEL](https://sugi.bio/atlas/gene/KEL/) |
| Protein change (HGVS p.) | p.Arg47Pro |
| Coding change (HGVS c.) | c.140G>C |
| MANE Select transcript | [NM_000420](https://www.ncbi.nlm.nih.gov/nuccore/NM_000420) |
| dbSNP | [rs370130119](https://www.ncbi.nlm.nih.gov/snp/rs370130119/) |
| Variant type | single nucleotide variant |
| Location | chr7:142961443-142961443 (GRCh38) |
| ClinVar | [VCV3113948](https://www.ncbi.nlm.nih.gov/clinvar/variation/3113948/) |

**All HGVS expressions:** `LRG_799:g.5974G>C`, `LRG_799t1:c.140G>C`, `NC_000007.13:g.142658530C>G`, `NC_000007.14:g.142961443C>G`, `NG_007492.3:g.5974G>C`, `NM_000420.3:c.140G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1873)
- REVEL 0.417 (indeterminate)
- SaProt LLR -12.118 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 0.518, GERP 3.2 — weakly conserved position
- CADD: **PHRED 18.68**. 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 1.00** across the covering region of the MANE Select transcript (142,941,255–142,962,206), spanning 20,951 bp. Chi-square p 0.95. 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>T, Δ0.21 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 (gnomAD v4.1): grpmax **0.0345%** (mid) · FAF95 0.00607% · FAF99 0.00251% · 2/5,796 in the highest group · 49/1,612,778 alleles overall — ultra-rare (popmax 0.0345%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0345% | 2,898 |
| Remaining individuals (not grpmax-eligible) | 0.00641% | 15,592 |
| European (non-Finnish) | 0.00356% | 28,088 |
| South Asian | 0.0011% | 90,904 |

*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}

**KEL** population constraint: LOEUF 1.11, pLI 6.9359e-31, missense-Z 0.50767. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.46, 64% of residues very-high.

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

*Describes the biological roles of KEL (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:** KEL's established molecular role includes metalloendopeptidase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |

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

**Molecular function:** metalloendopeptidase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-15.

**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 | 2025-10-15 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related KEL variant pages (same residue, condition, or type): [KEL p.Pro375Thr](/variant/kel-p-pro375thr), [KEL p.Arg516=](/variant/kel-p-arg516), [KEL p.Leu335=](/variant/kel-p-leu335), [KEL p.Leu597Pro](/variant/kel-p-leu597pro), [KEL p.Phe324=](/variant/kel-p-phe324), [KEL c.400+1G>A](/variant/kel-c-400-plus-1g-a), [KEL p.Ala148Gly](/variant/kel-p-ala148gly), [KEL p.Ala311Asp](/variant/kel-p-ala311asp).

### 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 3113948). 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.*