# NM_024692.6(CLIP4):c.1730G>A (p.Arg577Lys)

https://sugi.bio/variant/clip4-p-arg577lys

## Summary

**CLIP4 p.Arg577Lys (c.1730G>A)** is classified **Uncertain significance** in CLIP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.1611); Very rare (popmax 0.00224%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00224%, eas)

## For patients & families {#patients}

This is a change in the CLIP4 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 | [CLIP4](https://sugi.bio/atlas/gene/CLIP4/) |
| Protein change (HGVS p.) | p.Arg577Lys |
| Coding change (HGVS c.) | c.1730G>A |
| MANE Select transcript | [NM_018961](https://www.ncbi.nlm.nih.gov/nuccore/NM_018961) (variant reported on NM_024692) |
| Variant type | single nucleotide variant |
| Location | chr2:29174379-29174379 (GRCh38) |
| ClinVar | [VCV4003710](https://www.ncbi.nlm.nih.gov/clinvar/variation/4003710/) |

**All HGVS expressions:** `NC_000002.11:g.29397245G>A`, `NC_000002.12:g.29174379G>A`, `NM_001287527.2:c.1730G>A`, `NM_001287528.2:c.1730G>A`, `NM_001410747.1:c.1723+6839G>A`, `NM_024692.6:c.1730G>A`, `NR_109844.2:n.1789G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1611)
- REVEL 0.165 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.474 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.713, GERP 2.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.6**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.23 acceptor loss), 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 **0.00224%** (eas) · 1/44,696 in the highest group · 1/1,458,076 alleles overall — very rare (popmax 0.00224%, eas).

*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.*

## Protein context {#protein}

Residue **577** lies in the 'phosphatase-like' region.

AlphaFold model confidence (whole protein): pLDDT 82.62, 63% of residues very-high.

**2 experimental structure(s)** (PDB): [2CRN](https://www.rcsb.org/structure/2CRN), [5WDI](https://www.rcsb.org/structure/5WDI).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-20.

**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 | 2025-03-20 |

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

## Similar variants {#similar}

Related CLIP4 variant pages (same residue, condition, or type): [UBASH3A p.Pro577Leu](/variant/ubash3a-p-pro577leu), [UBASH3A p.Ile463Phe](/variant/ubash3a-p-ile463phe), [CLIP4 p.Thr555=](/variant/clip4-p-thr555), [UBASH3A c.1393+3A>C](/variant/ubash3a-c-1393-plus-3a-c), [UBASH3A p.Gly601=](/variant/ubash3a-p-gly601), [UBASH3A p.Ile303=](/variant/ubash3a-p-ile303), [UBASH3A p.Ile658Val](/variant/ubash3a-p-ile658val), [UBASH3A p.Phe304=](/variant/ubash3a-p-phe304).

### 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 4003710). 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.*