# NM_001007540.4(CDHR4):c.448C>T (p.Arg150Trp)

https://sugi.bio/variant/cdhr4-p-arg150trp

## Summary

**CDHR4 p.Arg150Trp (c.448C>T)** is classified **Uncertain significance** in CDHR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-13). AlphaMissense: likely benign (0.0885); Ultra-rare (popmax 0.0826%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs757284426 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0826%, mid)

## For patients & families {#patients}

This is a change in the CDHR4 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 | [CDHR4](https://sugi.bio/atlas/gene/CDHR4/) |
| Protein change (HGVS p.) | p.Arg150Trp |
| Coding change (HGVS c.) | c.448C>T |
| MANE Select transcript | [NM_001007540](https://www.ncbi.nlm.nih.gov/nuccore/NM_001007540) |
| dbSNP | [rs757284426](https://www.ncbi.nlm.nih.gov/snp/rs757284426/) |
| Variant type | single nucleotide variant |
| Location | chr3:49798873-49798873 (GRCh38) |
| ClinVar | [VCV3141402](https://www.ncbi.nlm.nih.gov/clinvar/variation/3141402/) |

**All HGVS expressions:** `NC_000003.11:g.49836306G>A`, `NC_000003.12:g.49798873G>A`, `NM_001007540.4:c.448C>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** (0.0885)
- REVEL 0.114 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.462 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.005, GERP -2.76 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 13.7**. 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 0.91** across the covering region of the MANE Select transcript (49,790,835–49,799,812), spanning 8,977 bp. Chi-square p 0.0033. 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>T, Δ0.24 donor loss), 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 **0.0826%** (mid) · FAF95 0.0535% · FAF99 0.0486% · 5/6,054 in the highest group · 158/1,613,860 alleles overall — ultra-rare (popmax 0.0826%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0826% | 1,211 |
| South Asian | 0.067% | 1,493 |
| Admixed American | 0.0533% | 1,875 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,810 |
| European (non-Finnish) | 0.00432% | 23,134 |
| African / African-American | 0.00133% | 75,026 |

*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}

**CDHR4** population constraint: LOEUF 1.174, pLI 3.2476e-30, missense-Z 1.4262. *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 78.90, 34% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-13.

**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 | 2023-12-13 |

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

## Similar variants {#similar}

Related CDHR4 variant pages (same residue, condition, or type): [CDHR4 p.Ala12Val](/variant/cdhr4-p-ala12val), [CDHR4 p.Ala149Val](/variant/cdhr4-p-ala149val), [CDHR4 p.Ala302Val](/variant/cdhr4-p-ala302val), [CDHR4 p.Ala310Pro](/variant/cdhr4-p-ala310pro), [CDHR4 p.Ala318Asp](/variant/cdhr4-p-ala318asp), [CDHR4 p.Ala341Pro](/variant/cdhr4-p-ala341pro), [CDHR4 p.Ala385Gly](/variant/cdhr4-p-ala385gly), [CDHR4 p.Ala456Pro](/variant/cdhr4-p-ala456pro).

### 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 3141402). 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.*