# NM_007272.3(CTRC):c.387G>A (p.Glu129=)

https://sugi.bio/variant/ctrc-p-glu129

## Summary

**CTRC p.Glu129= (c.387G>A)** is classified **Likely benign** in CTRC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-11). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary chronic pancreatitis.

**At a glance:** Likely benign · review: Single submitter · rsID rs1708165790 · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CTRC gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to hereditary chronic pancreatitis.

*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 |
| Age of onset (of this condition) | Adolescent, Childhood |
| Prevalence | 1-9 / 1 000 000 (France) |
| Clinical trials | 8 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Autosomal dominant hereditary chronic pancreatitis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Leukocytosis — Very frequent (99-80%)
- Abdominal pain — Very frequent (99-80%)
- Elevated circulating C-reactive protein concentration — Very frequent (99-80%)
- Recurrent pancreatitis — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Frequent (79-30%)
- Diabetes mellitus — Occasional (29-5%)
- Jaundice — Occasional (29-5%)
- Pancreatic calcification — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006632/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTRC](https://sugi.bio/atlas/gene/CTRC/) |
| Protein change (HGVS p.) | p.Glu129= |
| Coding change (HGVS c.) | c.387G>A |
| MANE Select transcript | [NM_007272](https://www.ncbi.nlm.nih.gov/nuccore/NM_007272) |
| dbSNP | [rs1708165790](https://www.ncbi.nlm.nih.gov/snp/rs1708165790/) |
| Variant type | single nucleotide variant |
| Location | chr1:15443449-15443449 (GRCh38) |
| ClinVar | [VCV1735786](https://www.ncbi.nlm.nih.gov/clinvar/variation/1735786/) |

**All HGVS expressions:** `NC_000001.10:g.15769944G>A`, `NC_000001.11:g.15443449G>A`, `NG_009253.1:g.10007G>A`, `NG_009253.2:g.10008G>A`, `NM_007272.3:c.387G>A`

## 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 0.619, GERP -4.81, phastCons 0.065 — weakly conserved position
- CADD: **PHRED 6.864**. 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, Δ0.29 acceptor 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 **8.47e-05%** (nfe) · 1/1,180,042 in the highest group · 1/1,461,884 alleles overall — very rare (popmax 8.47e-05%, 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}

**CTRC** population constraint: LOEUF 1.147, pLI 4.5697e-10, missense-Z 1.0022. *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 **129** lies in a disulfide bond; the peptidase s1 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 94.03, 92% of residues very-high.

**1 experimental structure(s)** (PDB): [4H4F](https://www.rcsb.org/structure/4H4F).

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

*Describes the biological roles of CTRC (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:** CTRC's established molecular role includes peptidase activity. p.Glu129= falls in the peptidase s1 domain.


### Pathways affected {#pathways}

CTRC participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Developmental Lineage of Pancreatic Acinar Cells](https://reactome.org/content/detail/R-HSA-9925561) | curated |

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

**Molecular function:** peptidase activity.

**Biological process:** proteolysis, intracellular calcium ion homeostasis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-11-11.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-11-11 |

## Associated conditions {#conditions}

[hereditary chronic pancreatitis](https://sugi.bio/atlas/disease/hereditary-chronic-pancreatitis/).

**Reported phenotype names (ClinVar):** Hereditary pancreatitis, Hereditary chronic pancreatitis, PRSS1-Related Hereditary Pancreatitis.

## Similar variants {#similar}

Related CTRC variant pages (same residue, condition, or type): [CTRC c.494-1G>C](/variant/ctrc-c-494-minus-1g-c), [CTRC p.Arg29Ter](/variant/ctrc-p-arg29ter), [CTRC p.Gln174Ter](/variant/ctrc-p-gln174ter), [CTRC c.356+1G>A](/variant/ctrc-c-356-plus-1g-a), [CTRC c.40+4A>G](/variant/ctrc-c-40-plus-4a-g), [CTRC c.40+6C>T](/variant/ctrc-c-40-plus-6c-t), [CTRC p.Ala12Val](/variant/ctrc-p-ala12val), [CTRC p.Ala184Val](/variant/ctrc-p-ala184val).

### 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 1735786). 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.*