# NM_007265.3(ECD):c.1921C>T (p.Pro641Ser)

https://sugi.bio/variant/ecd-p-pro641ser

## Summary

**ECD p.Pro641Ser (c.1921C>T)** is classified **Uncertain significance** in ECD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). AlphaMissense: likely benign (0.0755); Very rare (popmax 0.00373%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00373%, nfe)

## For patients & families {#patients}

This is a change in the ECD 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 | [ECD](https://sugi.bio/atlas/gene/ECD/) |
| Protein change (HGVS p.) | p.Pro641Ser |
| Coding change (HGVS c.) | c.1921C>T |
| MANE Select transcript | [NM_006304](https://www.ncbi.nlm.nih.gov/nuccore/NM_006304) (variant reported on NM_007265) |
| Variant type | single nucleotide variant |
| Location | chr10:73134597-73134597 (GRCh38) |
| ClinVar | [VCV3843269](https://www.ncbi.nlm.nih.gov/clinvar/variation/3843269/) |

**All HGVS expressions:** `NC_000010.10:g.74894355G>A`, `NC_000010.11:g.73134597G>A`, `NM_001135752.1:c.2020C>T`, `NM_001135753.1:c.1792C>T`, `NM_007265.3:c.1921C>T`, `NR_024203.1:n.1753C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0755)
- REVEL 0.104 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.747 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.261, GERP 2.23, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.83**. 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 assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00373%** (nfe) · FAF95 0.00283% · FAF99 0.00252% · 44/1,179,334 in the highest group · 45/1,612,976 alleles overall — very rare (popmax 0.00373%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00373% | 26,803 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,448 |

*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}

**ECD** population constraint: ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.87, 0% of residues very-high.

**140 experimental structure(s)** (PDB): [1IYJ](https://www.rcsb.org/structure/1IYJ), [1MIU](https://www.rcsb.org/structure/1MIU), [1MJE](https://www.rcsb.org/structure/1MJE), [3T5X](https://www.rcsb.org/structure/3T5X), [5GJQ](https://www.rcsb.org/structure/5GJQ), [5GJR](https://www.rcsb.org/structure/5GJR).

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

*Describes the biological roles of ECD (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:** ECD's established molecular role includes ubiquitin binding. In Reactome, ECD is annotated in disease pathway(s) including **Hh mutants are degraded by ERAD**, **Vif-mediated degradation of APOBEC3G**.

**Disease mechanism (Reactome):** ECD loss or alteration is curated in [Hh mutants are degraded by ERAD](https://reactome.org/content/detail/R-HSA-5362768), [Vif-mediated degradation of APOBEC3G](https://reactome.org/content/detail/R-HSA-180585), [Vpu mediated degradation of CD4](https://reactome.org/content/detail/R-HSA-180534).

### Pathways affected {#pathways}

ECD participates in **79 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Hh mutants are degraded by ERAD](https://reactome.org/content/detail/R-HSA-5362768) | curated |
| ⚕ [Vif-mediated degradation of APOBEC3G](https://reactome.org/content/detail/R-HSA-180585) | curated |
| ⚕ [Vpu mediated degradation of CD4](https://reactome.org/content/detail/R-HSA-180534) | curated |
| ⚕ [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895) | other |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | other |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | other |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | other |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | other |
| ⚕ [Impaired BRCA2 binding to SEM1 (DSS1)](https://reactome.org/content/detail/R-HSA-9763198) | other |
| ⚕ [Impaired BRCA2 translocation to the nucleus](https://reactome.org/content/detail/R-HSA-9709275) | other |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [APC/C:Cdc20 mediated degradation of Securin](https://reactome.org/content/detail/R-HSA-174154) | curated |
| [APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1](https://reactome.org/content/detail/R-HSA-174178) | curated |
| [AUF1 (hnRNP D0) binds and destabilizes mRNA](https://reactome.org/content/detail/R-HSA-450408) | curated |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | curated |
| [Asymmetric localization of PCP proteins](https://reactome.org/content/detail/R-HSA-4608870) | curated |
| [Autodegradation of Cdh1 by Cdh1:APC/C](https://reactome.org/content/detail/R-HSA-174084) | curated |
| [Autodegradation of the E3 ubiquitin ligase COP1](https://reactome.org/content/detail/R-HSA-349425) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Cdc20:Phospho-APC/C mediated degradation of Cyclin A](https://reactome.org/content/detail/R-HSA-174184) | curated |
| [Cross-presentation of soluble exogenous antigens (endosomes)](https://reactome.org/content/detail/R-HSA-1236978) | curated |
| [Dectin-1 mediated noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5607761) | curated |
| [Degradation of AXIN](https://reactome.org/content/detail/R-HSA-4641257) | curated |
| [Degradation of DVL](https://reactome.org/content/detail/R-HSA-4641258) | curated |
| [Degradation of GLI1 by the proteasome](https://reactome.org/content/detail/R-HSA-5610780) | curated |
| [Degradation of beta-catenin by the destruction complex](https://reactome.org/content/detail/R-HSA-195253) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | curated |
| [GLI3 is processed to GLI3R by the proteasome](https://reactome.org/content/detail/R-HSA-5610785) | curated |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | curated |
| [Hedgehog ligand biogenesis](https://reactome.org/content/detail/R-HSA-5358346) | curated |
| [Negative Regulation of DNA Double Strand Break Response](https://reactome.org/content/detail/R-HSA-9974237) | curated |
| [Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha](https://reactome.org/content/detail/R-HSA-1234176) | curated |
| [Regulation of RAS by GAPs](https://reactome.org/content/detail/R-HSA-5658442) | curated |
| [Regulation of ornithine decarboxylase (ODC)](https://reactome.org/content/detail/R-HSA-350562) | curated |
| [SCF(Skp2)-mediated degradation of p27/p21](https://reactome.org/content/detail/R-HSA-187577) | curated |
| [SCF-beta-TrCP mediated degradation of Emi1](https://reactome.org/content/detail/R-HSA-174113) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9931269) | other |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | other |
| [Assembly of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68867) | other |
| [CDK-mediated phosphorylation and removal of Cdc6](https://reactome.org/content/detail/R-HSA-69017) | other |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | other |
| [Degradation of CRY and PER proteins](https://reactome.org/content/detail/R-HSA-9932298) | other |
| [Degradation of GLI2 by the proteasome](https://reactome.org/content/detail/R-HSA-5610783) | electronic |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | electronic |
| [FBXL7 down-regulates AURKA during mitotic entry and in early mitosis](https://reactome.org/content/detail/R-HSA-8854050) | other |
| [G2/M Checkpoints](https://reactome.org/content/detail/R-HSA-69481) | other |
| [GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2](https://reactome.org/content/detail/R-HSA-9762114) | other |
| [GSK3B-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929356) | other |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | other |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | other |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | other |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | other |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | other |
| [NIK-->noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5676590) | other |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | other |
| [Negative regulation of NOTCH4 signaling](https://reactome.org/content/detail/R-HSA-9604323) | other |
| [Orc1 removal from chromatin](https://reactome.org/content/detail/R-HSA-68949) | other |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | other |
| [Proteasome assembly](https://reactome.org/content/detail/R-HSA-9907900) | other |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | other |
| [Regulation of PTEN stability and activity](https://reactome.org/content/detail/R-HSA-8948751) | other |
| [Regulation of RUNX2 expression and activity](https://reactome.org/content/detail/R-HSA-8939902) | other |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | other |
| [Regulation of activated PAK-2p34 by proteasome mediated degradation](https://reactome.org/content/detail/R-HSA-211733) | electronic |
| [Regulation of expression of SLITs and ROBOs](https://reactome.org/content/detail/R-HSA-9010553) | other |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | other |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | other |
| [Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide](https://reactome.org/content/detail/R-HSA-9954709) | other |
| [SPOP-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929491) | other |
| [Somitogenesis](https://reactome.org/content/detail/R-HSA-9824272) | other |
| [TNFR2 non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5668541) | other |
| [The role of GTSE1 in G2/M progression after G2 checkpoint](https://reactome.org/content/detail/R-HSA-8852276) | other |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | other |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | other |
| [Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A](https://reactome.org/content/detail/R-HSA-69601) | other |
| [Ubiquitin-dependent degradation of Cyclin D](https://reactome.org/content/detail/R-HSA-75815) | other |

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

**Molecular function:** ubiquitin binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-01.

**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 | 2025-02-01 |

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

## Similar variants {#similar}

Related ECD variant pages (same residue, condition, or type): [ECD p.Ala121Gly](/variant/ecd-p-ala121gly), [ECD p.Ala122Ser](/variant/ecd-p-ala122ser), [ECD p.Ala150Thr](/variant/ecd-p-ala150thr), [ECD p.Ala234Ser](/variant/ecd-p-ala234ser), [ECD p.Ala329Val](/variant/ecd-p-ala329val), [ECD p.Arg188Leu](/variant/ecd-p-arg188leu), [ECD p.Arg244Gln](/variant/ecd-p-arg244gln), [ECD p.Arg281Gln](/variant/ecd-p-arg281gln).

### 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 3843269). 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.*