# NM_004425.4(ECM1):c.231C>T (p.Pro77=)

https://sugi.bio/variant/ecm1-p-pro77

## Summary

**ECM1 p.Pro77= (c.231C>T)** is classified **Benign** in ECM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Low-frequency (popmax 2.65%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs115614690 · 2 submitters · low-frequency (popmax 2.65%, afr)

## For patients & families {#patients}

This is a change in the ECM1 gene that is classified as benign — not considered disease-causing, submitted by 2 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 | [ECM1](https://sugi.bio/atlas/gene/ECM1/) |
| Protein change (HGVS p.) | p.Pro77= |
| Coding change (HGVS c.) | c.231C>T |
| MANE Select transcript | [NM_004425](https://www.ncbi.nlm.nih.gov/nuccore/NM_004425) |
| dbSNP | [rs115614690](https://www.ncbi.nlm.nih.gov/snp/rs115614690/) |
| Variant type | single nucleotide variant |
| Location | chr1:150509929-150509929 (GRCh38) |
| ClinVar | [VCV772686](https://www.ncbi.nlm.nih.gov/clinvar/variation/772686/) |

**All HGVS expressions:** `NC_000001.10:g.150482405C>T`, `NC_000001.11:g.150509929C>T`, `NG_012062.1:g.6919C>T`, `NM_001202858.2:c.312C>T`, `NM_004425.4:c.231C>T`, `NM_022664.3:c.231C>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 -0.034, GERP -1.4 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.46**. 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 (C>G, Δ0.23 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 **2.65%** (afr) · FAF95 2.55% · FAF99 2.51% · 1,985/75,010 in the highest group · 2,183/1,614,084 alleles overall — low-frequency (popmax 2.65%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.65% | 38 |
| Remaining individuals (not grpmax-eligible) | 0.162% | 619 |
| Admixed American | 0.113% | 883 |
| Middle Eastern | 0.066% | 1,516 |
| South Asian | 0.0132% | 7,590 |
| European (non-Finnish) | 0.0011% | 90,768 |

*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}

**ECM1** population constraint: LOEUF 1.051, pLI 3.8236e-17, missense-Z 1.0007. *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 **77** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 69.05, 41% of residues very-high.

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

*Describes the biological roles of ECM1 (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:** ECM1's established molecular role includes protease binding. p.Pro77= falls in the disordered region.


### Pathways affected {#pathways}

ECM1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |

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

**Molecular function:** protease binding.

**Biological process:** positive regulation of endothelial cell proliferation, negative regulation of peptidase activity, negative regulation of bone mineralization, positive regulation of angiogenesis.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2019-12-31.

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

**Submission history:** 2 submissions (2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related ECM1 variant pages (same residue, condition, or type): [ECM1 p.Pro77Ser](/variant/ecm1-p-pro77ser), [ECM1 p.Arg254Ter](/variant/ecm1-p-arg254ter), [ECM1 p.Arg416Ter](/variant/ecm1-p-arg416ter), [ECM1 p.Arg476Ter](/variant/ecm1-p-arg476ter), [ECM1 p.Arg53Ter](/variant/ecm1-p-arg53ter), [ECM1 p.Cys269Tyr](/variant/ecm1-p-cys269tyr), [ECM1 c.122-3T>G](/variant/ecm1-c-122-minus-3t-g), [ECM1 p.Arg185His](/variant/ecm1-p-arg185his).

### 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 772686). 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.*