# NM_002234.4(KCNA5):c.917C>A (p.Pro306Gln)

https://sugi.bio/variant/kcna5-p-pro306gln

## Summary

**KCNA5 p.Pro306Gln (c.917C>A)** is classified **Conflicting classifications of pathogenicity** in KCNA5 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0729); Ultra-rare (popmax 0.099%, mid); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs527534559 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.099%, mid)

## For patients & families {#patients}

This is a change in the KCNA5 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, 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 | [KCNA5](https://sugi.bio/atlas/gene/KCNA5/) |
| Protein change (HGVS p.) | p.Pro306Gln |
| Coding change (HGVS c.) | c.917C>A |
| MANE Select transcript | [NM_002234](https://www.ncbi.nlm.nih.gov/nuccore/NM_002234) |
| dbSNP | [rs527534559](https://www.ncbi.nlm.nih.gov/snp/rs527534559/) |
| Variant type | single nucleotide variant |
| Location | chr12:5045064-5045064 (GRCh38) |
| ClinVar | [VCV1005634](https://www.ncbi.nlm.nih.gov/clinvar/variation/1005634/) |

**All HGVS expressions:** `NC_000012.11:g.5154230C>A`, `NC_000012.12:g.5045064C>A`, `NG_012198.1:g.6146C>A`, `NM_002234.2:c.917C>A`, `NM_002234.4:c.917C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0729)
- REVEL 0.297 (indeterminate)
- SaProt LLR -8.626 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 1.314, GERP -2.03, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 7.498**. 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 1.09** across the covering region of the MANE Select transcript (5,044,148–5,045,986), spanning 1,838 bp. Chi-square p 0.012. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.099%** (mid) · FAF95 0.043% · FAF99 0.0295% · 6/6,058 in the highest group · 86/1,612,630 alleles overall — ultra-rare (popmax 0.099%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.099% | 1,010 |
| Admixed American | 0.0267% | 3,747 |
| Remaining individuals (not grpmax-eligible) | 0.0176% | 5,679 |
| African / African-American | 0.008% | 12,501 |
| European (non-Finnish) | 0.00382% | 26,211 |
| South Asian | 0.0022% | 45,494 |

*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}

**KCNA5** population constraint: LOEUF 1.182, pLI 2.1099e-07, missense-Z -0.73659. *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 72.64, 46% of residues very-high.

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

*Describes the biological roles of KCNA5 (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:** KCNA5's established molecular role includes voltage-gated potassium channel activity.


### Pathways affected {#pathways}

KCNA5 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Phase 3 - rapid repolarisation](https://reactome.org/content/detail/R-HSA-5576890) | curated |
| [Voltage gated Potassium channels](https://reactome.org/content/detail/R-HSA-1296072) | curated |

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

**Molecular function:** voltage-gated potassium channel activity, delayed rectifier potassium channel activity, outward rectifier potassium channel activity, protein kinase binding, alpha-actinin binding, voltage-gated potassium channel activity involved in bundle of His cell action potential repolarization.

**Biological process:** potassium ion transport, regulation of membrane potential, membrane hyperpolarization, regulation of atrial cardiac muscle cell membrane repolarization, potassium ion transmembrane transport, atrial cardiac muscle cell action potential.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-20.

**Submitter consensus:** conflicting (4 Uncertain significance, 1 Likely benign).

**Submission history:** 5 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-15 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-08 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [atrial fibrillation, familial, 7](https://sugi.bio/atlas/disease/atrial-fibrillation-familial-7/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Atrial fibrillation, familial, 7, not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related KCNA5 variant pages (same residue, condition, or type): [KCNA5 p.Pro306Leu](/variant/kcna5-p-pro306leu), [KCNA5 c.-52G>T](/variant/kcna5-c-minus-52g-t), [KCNA5 c.*244C>T](/variant/kcna5-c-star-244c-t), [KCNA5 c.*782G>A](/variant/kcna5-c-star-782g-a), [KCNA5 p.Ala293Thr](/variant/kcna5-p-ala293thr), [KCNA5 p.Ala295Ser](/variant/kcna5-p-ala295ser), [KCNA5 p.Ala305Thr](/variant/kcna5-p-ala305thr), [KCNA5 p.Ala397Thr](/variant/kcna5-p-ala397thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1005634). 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.*