# NM_004898.4(CLOCK):c.451G>C (p.Asp151His)

https://sugi.bio/variant/clock-p-asp151his

## Summary

**CLOCK p.Asp151His (c.451G>C)** is classified **Uncertain significance** in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-21). AlphaMissense: ambiguous (0.4504); Very rare (popmax 0.00348%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs375936156 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00348%, nfe)

## For patients & families {#patients}

This is a change in the CLOCK 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 | [CLOCK](https://sugi.bio/atlas/gene/CLOCK/) |
| Protein change (HGVS p.) | p.Asp151His |
| Coding change (HGVS c.) | c.451G>C |
| MANE Select transcript | [NM_004898](https://www.ncbi.nlm.nih.gov/nuccore/NM_004898) |
| dbSNP | [rs375936156](https://www.ncbi.nlm.nih.gov/snp/rs375936156/) |
| Variant type | single nucleotide variant |
| Location | chr4:55463793-55463793 (GRCh38) |
| ClinVar | [VCV2379503](https://www.ncbi.nlm.nih.gov/clinvar/variation/2379503/) |

**All HGVS expressions:** `NC_000004.11:g.56329960C>G`, `NC_000004.12:g.55463793C>G`, `NM_001267843.2:c.451G>C`, `NM_004898.4:c.451G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4504) — no call either way
- REVEL 0.431 (indeterminate)
- SaProt LLR -9.059 (tolerated)
- SpliceAI predicts **acceptor loss** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.679, GERP 2.64, phastCons 1 — highly conserved
- CADD: **PHRED 29.8**. 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 0.82** across the covering region of the MANE Select transcript (55,458,917–55,482,785), spanning 23,868 bp. Chi-square p 0.0017. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00348%** (nfe) · FAF95 0.00259% · FAF99 0.00233% · 41/1,177,118 in the highest group · 44/1,609,558 alleles overall — very rare (popmax 0.00348%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00348% | 28,710 |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,135 |
| African / African-American | 0.00134% | 74,756 |

*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}

**CLOCK** population constraint: LOEUF 0.496, pLI 0.9683, missense-Z 1.6513. *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 **151** lies in the pas 1 domain.

AlphaFold model confidence (whole protein): pLDDT 61.90, 33% of residues very-high.

**2 experimental structure(s)** (PDB): [4H10](https://www.rcsb.org/structure/4H10), [6QPJ](https://www.rcsb.org/structure/6QPJ).

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

*Describes the biological roles of CLOCK (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:** CLOCK's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Asp151His falls in the pas 1 domain.


### Pathways affected {#pathways}

CLOCK participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [BMAL1:CLOCK,NPAS2 activates circadian expression](https://reactome.org/content/detail/R-HSA-1368108) | electronic |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | electronic |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | electronic |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | electronic |
| [Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes](https://reactome.org/content/detail/R-HSA-9931510) | electronic |
| [Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK](https://reactome.org/content/detail/R-HSA-9931529) | electronic |
| [Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters](https://reactome.org/content/detail/R-HSA-9931512) | electronic |
| [The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex](https://reactome.org/content/detail/R-HSA-9931521) | electronic |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA binding, histone acetyltransferase activity, E-box binding, sequence-specific double-stranded DNA binding.

**Biological process:** DNA damage checkpoint signaling, protein acetylation, circadian regulation of gene expression, regulation of hair cycle, positive regulation of circadian rhythm, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-21.

**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 | 2024-07-21 |

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

## Similar variants {#similar}

Related CLOCK variant pages (same residue, condition, or type): [CLOCK c.674-10A>G](/variant/clock-c-674-minus-10a-g), [CLOCK p.Ala34=](/variant/clock-p-ala34), [CLOCK p.Gly235Glu](/variant/clock-p-gly235glu), [CLOCK c.2362-2A>G](/variant/clock-c-2362-minus-2a-g), [CLOCK p.Ala432Pro](/variant/clock-p-ala432pro), [CLOCK p.Ala691Gly](/variant/clock-p-ala691gly), [CLOCK p.Arg242Lys](/variant/clock-p-arg242lys), [CLOCK p.Arg386Gln](/variant/clock-p-arg386gln).

### 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 2379503). 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.*