# NM_000075.4(CDK4):c.771G>A (p.Val257=)

https://sugi.bio/variant/cdk4-p-val257

## Summary

**CDK4 p.Val257= (c.771G>A)** is classified **Benign/Likely benign** in CDK4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.04%, afr); Associated with familial melanoma.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs377612647 · 6 submitters · 3 linked conditions · ultra-rare (popmax 0.04%, afr)

## For patients & families {#patients}

This is a change in the CDK4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 submitters, and is linked to familial melanoma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Multigenic/multifactorial |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Familial melanoma** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Melanoma — Very frequent (99-80%)
- Nevus — Very frequent (99-80%)
- Dry skin — Frequent (79-30%)
- Freckling — Frequent (79-30%)
- Abnormality of the hair — Frequent (79-30%)
- Abnormality of the lymphatic system — Frequent (79-30%)
- Retinopathy — Occasional (29-5%)
- Abnormality of extrapyramidal motor function — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003460/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDK4](https://sugi.bio/atlas/gene/CDK4/) |
| Protein change (HGVS p.) | p.Val257= |
| Coding change (HGVS c.) | c.771G>A |
| MANE Select transcript | [NM_005981](https://www.ncbi.nlm.nih.gov/nuccore/NM_005981) (variant reported on NM_000075) |
| dbSNP | [rs377612647](https://www.ncbi.nlm.nih.gov/snp/rs377612647/) |
| Variant type | single nucleotide variant |
| Location | chr12:57749230-57749230 (GRCh38) |
| ClinVar | [VCV219393](https://www.ncbi.nlm.nih.gov/clinvar/variation/219393/) |

**All HGVS expressions:** `LRG_490:g.8152G>A`, `LRG_490t1:c.771G>A`, `NC_000012.11:g.58143013C>T`, `NC_000012.12:g.57749230C>T`, `NG_007484.2:g.8152G>A`, `NM_000075.4:c.771G>A`, `NM_001330168.2:c.*1940C>T`, `NM_001330169.2:c.*1940C>T`, `NM_005981.5:c.*1940C>T`

## 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 1.314, GERP -1.42, phastCons 1 — weakly conserved position
- CADD: **PHRED 11.44**. 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 looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.04%** (afr) · FAF95 0.0288% · FAF99 0.0249% · 30/75,068 in the highest group · 49/1,614,084 alleles overall — ultra-rare (popmax 0.04%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.04% | 2,502 |
| East Asian | 0.00446% | 22,443 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,248 |
| Admixed American | 0.00167% | 60,020 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,050 |
| European (non-Finnish) | 0.0011% | 90,763 |

*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.*

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-13.

**Submitter consensus:** conflicting (4 Likely benign, 2 Benign).

**Submission history:** 6 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Benign | criteria provided, single submitter | clinical testing | 2020-03-09 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-02-12 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-09-26 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-01 |

## Associated conditions {#conditions}

[familial melanoma](https://sugi.bio/atlas/disease/familial-melanoma/), [melanoma, cutaneous malignant, susceptibility to, 3](https://sugi.bio/atlas/disease/melanoma-cutaneous-malignant-susceptibility-to-3/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Familial melanoma, Hereditary cancer-predisposing syndrome, not specified, not provided, Melanoma, cutaneous malignant, susceptibility to, 3, Hereditary melanoma, Hereditary cutaneous melanoma, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition.

### 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 2026-07-14); 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 219393). 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.*