# NM_022476.4(AKTIP):c.41A>G (p.Lys14Arg)

https://sugi.bio/variant/aktip-p-lys14arg

## Summary

**AKTIP p.Lys14Arg (c.41A>G)** is classified **Uncertain significance** in AKTIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.0847); Very rare (popmax 0.00238%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00238%, nfe)

## For patients & families {#patients}

This is a change in the AKTIP 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 | [AKTIP](https://sugi.bio/atlas/gene/AKTIP/) |
| Protein change (HGVS p.) | p.Lys14Arg |
| Coding change (HGVS c.) | c.41A>G |
| MANE Select transcript | [NM_022476](https://www.ncbi.nlm.nih.gov/nuccore/NM_022476) |
| Variant type | single nucleotide variant |
| Location | chr16:53500219-53500219 (GRCh38) |
| ClinVar | [VCV3850921](https://www.ncbi.nlm.nih.gov/clinvar/variation/3850921/) |

**All HGVS expressions:** `NC_000016.10:g.53500219T>C`, `NC_000016.9:g.53534131T>C`, `NM_001012398.3:c.41A>G`, `NM_001308325.2:c.41A>G`, `NM_022476.4:c.41A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0847)
- REVEL 0.392 (indeterminate)
- SaProt LLR -5.508 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.788, GERP 2.65, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.0**. 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 0.67** across the covering region of the MANE Select transcript (53,495,163–53,500,259), spanning 5,096 bp. Chi-square p 0.00012. 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 (T>A, Δ0.38 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 **0.00238%** (nfe) · FAF95 0.00165% · FAF99 0.00142% · 28/1,177,372 in the highest group · 28/1,457,702 alleles overall — very rare (popmax 0.00238%, nfe).

*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}

**AKTIP** population constraint: LOEUF 0.612, pLI 0.37378, missense-Z 2.0383. *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 **14** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 78.45, 60% of residues very-high.

**1 experimental structure(s)** (PDB): [8QAT](https://www.rcsb.org/structure/8QAT).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-11.

**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 | 2024-12-11 |

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

## Similar variants {#similar}

Related AKTIP variant pages (same residue, condition, or type): [AKTIP p.Ala235Thr](/variant/aktip-p-ala235thr), [AKTIP p.Ala47Val](/variant/aktip-p-ala47val), [AKTIP p.Arg101His](/variant/aktip-p-arg101his), [AKTIP p.Arg101Ser](/variant/aktip-p-arg101ser), [AKTIP p.Arg113Gln](/variant/aktip-p-arg113gln), [AKTIP p.Arg139Cys](/variant/aktip-p-arg139cys), [AKTIP p.Arg13Cys](/variant/aktip-p-arg13cys), [AKTIP p.Asp205Gly](/variant/aktip-p-asp205gly).

### 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 3850921). 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.*