# NM_198799.4(BCAS4):c.167G>A (p.Arg56Lys)

https://sugi.bio/variant/bcas4-p-arg56lys

## Summary

**BCAS4 p.Arg56Lys (c.167G>A)** is classified **Uncertain significance** in BCAS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-23). AlphaMissense: ambiguous (0.5015); Very rare (popmax 0.000509%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1402485852 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.000509%, nfe)

## For patients & families {#patients}

This is a change in the BCAS4 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 | [BCAS4](https://sugi.bio/atlas/gene/BCAS4/) |
| Protein change (HGVS p.) | p.Arg56Lys |
| Coding change (HGVS c.) | c.167G>A |
| MANE Select transcript | [NM_198799](https://www.ncbi.nlm.nih.gov/nuccore/NM_198799) |
| dbSNP | [rs1402485852](https://www.ncbi.nlm.nih.gov/snp/rs1402485852/) |
| Variant type | single nucleotide variant |
| Location | chr20:50830283-50830283 (GRCh38) |
| ClinVar | [VCV2477848](https://www.ncbi.nlm.nih.gov/clinvar/variation/2477848/) |

**All HGVS expressions:** `NC_000020.10:g.49446820G>A`, `NC_000020.11:g.50830283G>A`, `NM_001010974.3:c.167G>A`, `NM_017843.5:c.167G>A`, `NM_198799.4:c.167G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5015) — no call either way
- REVEL 0.197 (benign-leaning)
- SaProt LLR -8.369 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.40) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.654, GERP -0.479, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R86K** vs ClinVar **R56K**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 24.0**. 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 0.94** across the covering region of the MANE Select transcript (50,795,084–50,876,605), spanning 81,521 bp. Chi-square p 0.36. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.40**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.40**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,179,454 in the highest group · 6/1,461,164 alleles overall — very rare (popmax 0.000509%, 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}

**BCAS4** population constraint: LOEUF 1.081, pLI 0.010326, missense-Z 0.15306. *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 **56** lies in a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 72.40, 36% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-23.

**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 | 2023-01-23 |

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

## Similar variants {#similar}

Related BCAS4 variant pages (same residue, condition, or type): [BCAS4 p.Ser130Thr](/variant/bcas4-p-ser130thr), [BCAS4 p.Ser130Tyr](/variant/bcas4-p-ser130tyr), [BCAS4 p.Thr142Met](/variant/bcas4-p-thr142met), [BCAS4 c.-15C>T](/variant/bcas4-c-minus-15c-t), [BCAS4 c.-6C>T](/variant/bcas4-c-minus-6c-t), [BCAS4 p.Ala118Ser](/variant/bcas4-p-ala118ser), [BCAS4 p.Ala126Thr](/variant/bcas4-p-ala126thr), [BCAS4 p.Ala29Ser](/variant/bcas4-p-ala29ser).

### 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 2477848). 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.*