# NM_017679.5(BCAS3):c.1655C>T (p.Pro552Leu)

https://sugi.bio/variant/bcas3-p-pro552leu

## Summary

**BCAS3 p.Pro552Leu (c.1655C>T)** is classified **Pathogenic/Likely pathogenic** in BCAS3 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2023-09-12). AlphaMissense: likely benign (0.1178); Very rare (popmax 0.00297%, nfe); Associated with Global developmental delay.

**At a glance:** Pathogenic/Likely pathogenic · review: No assertion criteria · rsID rs754857276 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00297%, nfe)

## For patients & families {#patients}

This is a change in the BCAS3 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Global developmental delay.

*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 | [BCAS3](https://sugi.bio/atlas/gene/BCAS3/) |
| Protein change (HGVS p.) | p.Pro552Leu |
| Coding change (HGVS c.) | c.1655C>T |
| dbSNP | [rs754857276](https://www.ncbi.nlm.nih.gov/snp/rs754857276/) |
| Variant type | single nucleotide variant |
| Location | chr17:61034683-61034683 (GRCh38) |
| ClinVar | [VCV993270](https://www.ncbi.nlm.nih.gov/clinvar/variation/993270/) |

**All HGVS expressions:** `NC_000017.10:g.59112044C>T`, `NC_000017.11:g.61034683C>T`, `NM_001099432.3:c.1700C>T`, `NM_001320470.3:c.1655C>T`, `NM_001330413.2:c.1700C>T`, `NM_001330414.2:c.1655C>T`, `NM_001353144.2:c.1790C>T`, `NM_001353145.2:c.1745C>T`, `NM_001353146.2:c.1700C>T`, `NM_017679.5:c.1655C>T`, `NR_186505.1:n.572G>A`, `NR_186506.1:n.529G>A`, `NR_186507.1:n.1420G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1178) — ⚠ discordant with the pathogenic call
- REVEL 0.194 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.152 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.009, GERP 2.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P567L** vs ClinVar **P552L**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 26.6**. 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 0.79** across the covering region of the MANE Select transcript (60,679,458–61,368,344), spanning 688,886 bp. Chi-square p 8.1e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00297%** (nfe) · FAF95 0.00216% · FAF99 0.00191% · 35/1,176,512 in the highest group · 39/1,608,414 alleles overall — very rare (popmax 0.00297%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,775 |
| European (non-Finnish) (grpmax) | 0.00297% | 33,615 |
| Admixed American | 0.00168% | 59,518 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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.*

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2023-09-12.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2021–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Section for Clinical Neurogenetics, University of Tübingen | Likely pathogenic | no assertion criteria provided | research | 2021-01-12 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2023-09-12 |

## Associated conditions {#conditions}

[Global developmental delay](https://sugi.bio/atlas/disease/global-developmental-delay/), [Hengel-Maroofian-Schols syndrome](https://sugi.bio/atlas/disease/hengel-maroofian-schols-syndrome/).

**Reported phenotype names (ClinVar):** Global developmental delay, Hengel-Maroofian-Schols syndrome, Cognitive delay, NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, FACIAL DYSMORPHISM, AND BRAIN ABNORMALITIES, Global developmental delay-intellectual disability-microcephaly-short stature-brain iron accumulation syndrome.

### 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 993270). 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.*