# NM_173177.3(C1D):c.12A>G (p.Glu4=)

https://sugi.bio/variant/c1d-p-glu4

## Summary

**C1D p.Glu4= (c.12A>G)** is classified **Benign** in C1D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-04-16). Low-frequency (popmax 4.51%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs72906856 · 3 submitters · low-frequency (popmax 4.51%, afr)

## For patients & families {#patients}

This is a change in the C1D gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*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 | [C1D](https://sugi.bio/atlas/gene/C1D/) |
| Protein change (HGVS p.) | p.Glu4= |
| Coding change (HGVS c.) | c.12A>G |
| MANE Select transcript | [NM_173177](https://www.ncbi.nlm.nih.gov/nuccore/NM_173177) |
| dbSNP | [rs72906856](https://www.ncbi.nlm.nih.gov/snp/rs72906856/) |
| Variant type | single nucleotide variant |
| Location | chr2:68047299-68047299 (GRCh38) |
| ClinVar | [VCV787002](https://www.ncbi.nlm.nih.gov/clinvar/variation/787002/) |

**All HGVS expressions:** `NC_000002.11:g.68274431T>C`, `NC_000002.12:g.68047299T>C`, `NM_001190263.2:c.12A>G`, `NM_001190265.2:c.12A>G`, `NM_006333.4:c.12A>G`, `NM_173177.3:c.12A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.447, phastCons 1 — weakly conserved position
- CADD: **PHRED 10.53**. 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 deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.03**. Largest is acceptor loss, 16 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.03**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **4.51%** (afr) · FAF95 4.39% · FAF99 4.33% · 3,374/74,756 in the highest group · 4,322/1,609,026 alleles overall — low-frequency (popmax 4.51%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 4.51% | 22 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.04% | 96 |
| Remaining individuals (not grpmax-eligible) | 0.37% | 271 |
| Admixed American | 0.353% | 283 |
| Middle Eastern | 0.116% | 863 |
| European (non-Finnish) | 0.016% | 6,268 |
| South Asian | 0.0067% | 14,927 |
| Finnish (not grpmax-eligible) | 0.00157% | 63,722 |

*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}

**C1D** population constraint: LOEUF 0.826, pLI 0.64662, missense-Z 0.2371. *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 **4** lies in the 'required for transcriptional repression' region.

AlphaFold model confidence (whole protein): pLDDT 88.37, 67% of residues very-high.

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

*Describes the biological roles of C1D (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:** C1D's established molecular role includes RNA binding. p.Glu4= falls in the required for transcriptional repression region.


### Pathways affected {#pathways}

C1D participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Major pathway of rRNA processing in the nucleolus and cytosol](https://reactome.org/content/detail/R-HSA-6791226) | curated |
| [Nuclear RNA decay](https://reactome.org/content/detail/R-HSA-9930044) | curated |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

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

**Molecular function:** RNA binding.

**Biological process:** maturation of 5.8S rRNA.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-04-16.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 6 submissions (2018); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-04-16 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not provided, Uterine corpus endometrial carcinoma, Colon adenocarcinoma, Sarcoma, Malignant tumor of esophagus, none provided.

## Similar variants {#similar}

Related C1D variant pages (same residue, condition, or type): [LRP1 p.Ala1564Thr](/variant/lrp1-p-ala1564thr), [LRP1 p.Arg228Gln](/variant/lrp1-p-arg228gln), [LRP1 p.Arg2440Trp](/variant/lrp1-p-arg2440trp), [LRP1 p.Arg539Gln](/variant/lrp1-p-arg539gln), [LRP1 p.Asp4483Tyr](/variant/lrp1-p-asp4483tyr), [LRP1 p.Ser2907Pro](/variant/lrp1-p-ser2907pro), [LRP1 p.Val3296Ile](/variant/lrp1-p-val3296ile), [LRP1 c.10014+86A>G](/variant/lrp1-c-10014-plus-86a-g).

### 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 787002). 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.*