# NM_001077415.3(CRELD1):c.460C>T (p.Pro154Ser)

https://sugi.bio/variant/creld1-p-pro154ser

## Summary

**CRELD1 p.Pro154Ser (c.460C>T)** is classified **Uncertain significance** in CRELD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-27). AlphaMissense: likely benign (0.085); Ultra-rare (popmax 0.0121%, sas); Associated with atrioventricular septal defect, susceptibility to, 2.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs746095271 · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0121%, sas)

## For patients & families {#patients}

This is a change in the CRELD1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to atrioventricular septal defect, susceptibility to, 2.

*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 | [CRELD1](https://sugi.bio/atlas/gene/CRELD1/) |
| Protein change (HGVS p.) | p.Pro154Ser |
| Coding change (HGVS c.) | c.460C>T |
| MANE Select transcript | [NM_001077415](https://www.ncbi.nlm.nih.gov/nuccore/NM_001077415) |
| dbSNP | [rs746095271](https://www.ncbi.nlm.nih.gov/snp/rs746095271/) |
| Variant type | single nucleotide variant |
| Location | chr3:9938106-9938106 (GRCh38) |
| ClinVar | [VCV956320](https://www.ncbi.nlm.nih.gov/clinvar/variation/956320/) |

**All HGVS expressions:** `NC_000003.11:g.9979790C>T`, `NC_000003.12:g.9938106C>T`, `NG_017069.1:g.9266C>T`, `NM_001031717.4:c.460C>T`, `NM_001077415.3:c.460C>T`, `NM_001374316.1:c.460C>T`, `NM_001374317.1:c.460C>T`, `NM_001374318.1:c.460C>T`, `NM_001374319.1:c.460C>T`, `NM_001374320.1:c.460C>T`, `NM_015513.6:c.460C>T`, `NR_164475.1:n.498C>T`, `NR_164477.1:n.848C>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** (0.085)
- REVEL 0.021 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.352 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.522, GERP -3.39, phastCons 0.875 — weakly conserved position
- CADD: **PHRED 19.43**. 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 0.92** across the covering region of the MANE Select transcript (9,934,439–9,944,576), spanning 10,137 bp. Chi-square p 0.081. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.22 donor 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 **0.0121%** (sas) · FAF95 0.00677% · FAF99 0.00522% · 11/91,042 in the highest group · 34/1,612,522 alleles overall — ultra-rare (popmax 0.0121%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0121% | 8,277 |
| East Asian | 0.00669% | 14,959 |
| Admixed American | 0.00333% | 29,995 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,448 |
| European (non-Finnish) | 0.00144% | 69,377 |

*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}

**CRELD1** population constraint: LOEUF 0.885, pLI 7.6352e-10, missense-Z 0.96935. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **congenital heart disease** — Limited (AD)

## Protein context {#protein}

Residue **154** lies in the egf-like 1 domain.

AlphaFold model confidence (whole protein): pLDDT 81.68, 57% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-06-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-06-27 |

## Associated conditions {#conditions}

[atrioventricular septal defect, susceptibility to, 2](https://sugi.bio/atlas/disease/atrioventricular-septal-defect-susceptibility-to-2/).

**Reported phenotype names (ClinVar):** Atrioventricular septal defect, susceptibility to, 2.

## Similar variants {#similar}

Related CRELD1 variant pages (same residue, condition, or type): [CRELD1 c.1049-283C>T](/variant/creld1-c-1049-minus-283c-t), [CRELD1 c.1049-376T>G](/variant/creld1-c-1049-minus-376t-g), [CRELD1 c.1049-401C>T](/variant/creld1-c-1049-minus-401c-t), [CRELD1 p.Arg107Cys](/variant/creld1-p-arg107cys), [CRELD1 p.Arg175Gln](/variant/creld1-p-arg175gln), [CRELD1 p.Asn72Ser](/variant/creld1-p-asn72ser), [CRELD1 p.Cys221Arg](/variant/creld1-p-cys221arg), [CRELD1 p.Cys292Arg](/variant/creld1-p-cys292arg).

### 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 956320). 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.*