# NM_005235.3(ERBB4):c.64C>T (p.Pro22Ser)

https://sugi.bio/variant/erbb4-p-pro22ser

## Summary

**ERBB4 p.Pro22Ser (c.64C>T)** is classified **Uncertain significance** in ERBB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). AlphaMissense: likely benign (0.0664); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the ERBB4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [ERBB4](https://sugi.bio/atlas/gene/ERBB4/) |
| Protein change (HGVS p.) | p.Pro22Ser |
| Coding change (HGVS c.) | c.64C>T |
| MANE Select transcript | [NM_005235](https://www.ncbi.nlm.nih.gov/nuccore/NM_005235) |
| Variant type | single nucleotide variant |
| Location | chr2:212538467-212538467 (GRCh38) |
| ClinVar | [VCV3845728](https://www.ncbi.nlm.nih.gov/clinvar/variation/3845728/) |

**All HGVS expressions:** `NC_000002.11:g.213403191G>A`, `NC_000002.12:g.212538467G>A`, `NG_011805.2:g.5162C>T`, `NM_001042599.2:c.64C>T`, `NM_005235.3:c.64C>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** (0.0664)
- REVEL 0.097 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.521 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 9.639, GERP 1.11, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.9**. 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 0.75** across the covering region of the MANE Select transcript (211,702,031–212,538,530), spanning 836,499 bp. Chi-square p 7.9e-10. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/59,996 in the highest group · 3/1,613,850 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 29,998 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,476 |

*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}

**ERBB4** population constraint: LOEUF 0.357, pLI 1, missense-Z 2.8306; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *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):

- **amyotrophic lateral sclerosis type 19** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.17, 45% of residues very-high.

**14 experimental structure(s)** (PDB): [2AHX](https://www.rcsb.org/structure/2AHX), [2L2T](https://www.rcsb.org/structure/2L2T), [2LCX](https://www.rcsb.org/structure/2LCX), [2R4B](https://www.rcsb.org/structure/2R4B), [3BBT](https://www.rcsb.org/structure/3BBT), [3BBW](https://www.rcsb.org/structure/3BBW).

## What this gene does {#gene-function}

*Describes the biological roles of ERBB4 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ERBB4's established molecular role includes transcription cis-regulatory region binding. In Reactome, ERBB4 is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Signaling by ERBB2 KD Mutants**.

**Disease mechanism (Reactome):** ERBB4 loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565), [Signaling by ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665686).

### Pathways affected {#pathways}

ERBB4 participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | other |
| ⚕ [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565) | other |
| ⚕ [Signaling by ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665686) | other |
| [Downregulation of ERBB2 signaling](https://reactome.org/content/detail/R-HSA-8863795) | other |
| [Downregulation of ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1253288) | other |
| [ERBB2 Activates PTK6 Signaling](https://reactome.org/content/detail/R-HSA-8847993) | other |
| [ERBB2 Regulates Cell Motility](https://reactome.org/content/detail/R-HSA-6785631) | other |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | other |
| [GRB2 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963640) | other |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | other |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | other |
| [PI3K events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963642) | other |
| [PI3K events in ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1250342) | other |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | other |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | other |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | other |
| [SHC1 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1250196) | other |
| [SHC1 events in ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1250347) | other |
| [Signaling by ERBB2](https://reactome.org/content/detail/R-HSA-1227986) | other |
| [Signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1236394) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription cis-regulatory region binding, protein tyrosine kinase activity, transmembrane receptor protein tyrosine kinase activity, epidermal growth factor receptor binding, neuregulin receptor activity, protein homodimerization activity.

**Biological process:** signal transduction, cell surface receptor protein tyrosine kinase signaling pathway, lactation, positive regulation of cell population proliferation, negative regulation of cell population proliferation, cell migration.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-04.

**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 | 2025-03-04 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related ERBB4 variant pages (same residue, condition, or type): [ERBB4 p.Arg393Gln](/variant/erbb4-p-arg393gln), [ERBB4 p.Gln598Lys](/variant/erbb4-p-gln598lys), [ERBB4 p.Glu1138Gly](/variant/erbb4-p-glu1138gly), [ERBB4 p.Glu696Ala](/variant/erbb4-p-glu696ala), [ERBB4 p.Ile337Val](/variant/erbb4-p-ile337val), [ERBB4 p.Lys291Arg](/variant/erbb4-p-lys291arg), [ERBB4 p.Lys681Arg](/variant/erbb4-p-lys681arg), [ERBB4 p.Lys873Thr](/variant/erbb4-p-lys873thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3845728). 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.*