# NM_004445.6(EPHB6):c.1012C>T (p.Arg338Cys)

https://sugi.bio/variant/ephb6-p-arg338cys

## Summary

**EPHB6 p.Arg338Cys (c.1012C>T)** is classified **Uncertain significance** in EPHB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the EPHB6 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 | [EPHB6](https://sugi.bio/atlas/gene/EPHB6/) |
| Protein change (HGVS p.) | p.Arg338Cys |
| Coding change (HGVS c.) | c.1012C>T |
| MANE Select transcript | [NM_004445](https://www.ncbi.nlm.nih.gov/nuccore/NM_004445) |
| Variant type | single nucleotide variant |
| Location | chr7:142865537-142865537 (GRCh38) |
| ClinVar | [VCV3845482](https://www.ncbi.nlm.nih.gov/clinvar/variation/3845482/) |

**All HGVS expressions:** `NC_000007.13:g.142563292C>T`, `NC_000007.14:g.142865537C>T`, `NM_001280794.3:c.133C>T`, `NM_001280795.2:c.133C>T`, `NM_004445.6:c.1012C>T`, `NR_104001.2:n.1037C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.916, GERP -0.396, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 26.4**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.27 acceptor 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 **0.0165%** (mid) · FAF95 0.0145% · FAF99 0.0138% · 1/6,060 in the highest group · 212/1,613,424 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,060 |
| European (non-Finnish) | 0.0164% | 6,082 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,246 |
| African / African-American | 0.00801% | 12,486 |
| South Asian | 0.0011% | 91,074 |

*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}

**EPHB6** population constraint: LOEUF 0.607, pLI 1.8466e-05, missense-Z 2.5377. *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 81.36, 46% of residues very-high.

**1 experimental structure(s)** (PDB): [7K7J](https://www.rcsb.org/structure/7K7J).

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

*Describes the biological roles of EPHB6 (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.*


### Pathways affected {#pathways}

EPHB6 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | curated |
| [EPH-Ephrin signaling](https://reactome.org/content/detail/R-HSA-2682334) | electronic |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | electronic |
| [Ephrin signaling](https://reactome.org/content/detail/R-HSA-3928664) | electronic |

## Clinical significance {#significance}

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

**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 | 2024-12-12 |

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

## Similar variants {#similar}

Related EPHB6 variant pages (same residue, condition, or type): [TRPV6 p.Arg390Cys](/variant/trpv6-p-arg390cys), [EPHB6 p.Arg905Gln](/variant/ephb6-p-arg905gln), [EPHB6 p.Ala341Pro](/variant/ephb6-p-ala341pro), [EPHB6 p.Ala341Ser](/variant/ephb6-p-ala341ser), [EPHB6 p.Ala341Thr](/variant/ephb6-p-ala341thr), [EPHB6 p.Ala453Ser](/variant/ephb6-p-ala453ser), [EPHB6 p.Ala567Val](/variant/ephb6-p-ala567val), [EPHB6 p.Ala617Gly](/variant/ephb6-p-ala617gly).

### 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 3845482). 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.*