# NM_207406.4(BEND4):c.459C>A (p.Ser153Arg)

https://sugi.bio/variant/bend4-p-ser153arg

## Summary

**BEND4 p.Ser153Arg (c.459C>A)** is classified **Uncertain significance** in BEND4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). AlphaMissense: likely benign (0.2373); No allele count reported in gnomAD v4.1 (AN 1,506,130).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 1,506,130)

## For patients & families {#patients}

This is a change in the BEND4 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 | [BEND4](https://sugi.bio/atlas/gene/BEND4/) |
| Protein change (HGVS p.) | p.Ser153Arg |
| Coding change (HGVS c.) | c.459C>A |
| MANE Select transcript | [NM_207406](https://www.ncbi.nlm.nih.gov/nuccore/NM_207406) |
| Variant type | single nucleotide variant |
| Location | chr4:42151685-42151685 (GRCh38) |
| ClinVar | [VCV3824175](https://www.ncbi.nlm.nih.gov/clinvar/variation/3824175/) |

**All HGVS expressions:** `NC_000004.11:g.42153702G>T`, `NC_000004.12:g.42151685G>T`, `NG_102582.1:g.657G>T`, `NM_001159547.2:c.459C>A`, `NM_207406.4:c.459C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2373)
- REVEL 0.032 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.282 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.468, GERP 0.787, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.2**. 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 1.01** across the covering region of the MANE Select transcript (42,117,521–42,152,143), spanning 34,622 bp. Chi-square p 0.85. 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 (G>C, Δ0.29 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: **no allele count reported in gnomAD v4.1 (AN 1,506,130)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**BEND4** population constraint: LOEUF 0.756, pLI 0.00038482, missense-Z -1.0549. *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 60.57, 21% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-31.

**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 | 2024-12-31 |

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

## Similar variants {#similar}

Related BEND4 variant pages (same residue, condition, or type): [BEND4 p.Gln224Glu](/variant/bend4-p-gln224glu), [BEND4 p.Ser268Leu](/variant/bend4-p-ser268leu), [BEND4 p.Pro473=](/variant/bend4-p-pro473), [BEND4 p.Ala125Thr](/variant/bend4-p-ala125thr), [BEND4 p.Ala244Pro](/variant/bend4-p-ala244pro), [BEND4 p.Ala518Pro](/variant/bend4-p-ala518pro), [BEND4 p.Ala66Val](/variant/bend4-p-ala66val), [BEND4 p.Ala82Pro](/variant/bend4-p-ala82pro).

### 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 3824175). 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.*