# NM_000424.4(KRT5):c.259T>G (p.Phe87Val)

https://sugi.bio/variant/krt5-p-phe87val

## Summary

**KRT5 p.Phe87Val (c.259T>G)** is classified **Benign** in KRT5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1651); Common (popmax 5.76%, afr) — too common for a highly-penetrant pathogenic allele; Associated with epidermolysis bullosa simplex.

**At a glance:** Benign · review: Multiple submitters · rsID rs61747188 · 5 submitters · 1 linked condition · AlphaMissense likely benign · common (popmax 5.76%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the KRT5 gene that is classified as benign — not considered disease-causing, submitted by 5 submitters, and is linked to epidermolysis bullosa simplex.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 18 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010752/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [KRT5](https://sugi.bio/atlas/gene/KRT5/) |
| Protein change (HGVS p.) | p.Phe87Val |
| Coding change (HGVS c.) | c.259T>G |
| MANE Select transcript | [NM_000424](https://www.ncbi.nlm.nih.gov/nuccore/NM_000424) |
| dbSNP | [rs61747188](https://www.ncbi.nlm.nih.gov/snp/rs61747188/) |
| Variant type | single nucleotide variant |
| Location | chr12:52520038-52520038 (GRCh38) |
| ClinVar | [VCV309571](https://www.ncbi.nlm.nih.gov/clinvar/variation/309571/) |

**All HGVS expressions:** `NC_000012.11:g.52913822A>C`, `NC_000012.12:g.52520038A>C`, `NG_008297.1:g.5422T>G`, `NM_000424.4:c.259T>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.76%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.1651)
- REVEL 0.028 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.27 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.042, phastCons 0.029 — weakly conserved position
- CADD: **PHRED 15.6**. 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 0.98** across the covering region of the MANE Select transcript (52,518,975–52,520,296), spanning 1,321 bp. Chi-square p 0.7. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for KRT5 (205 scored positions, the nearest 112 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **5.76%** (afr) · FAF95 5.62% · FAF99 5.56% · 4,309/74,768 in the highest group · 4,755/1,613,422 alleles overall — common (popmax 5.76%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 5.76% | 17 |
| Remaining individuals (not grpmax-eligible) | 0.365% | 274 |
| Admixed American | 0.285% | 351 |
| Middle Eastern | 0.0825% | 1,212 |
| South Asian | 0.0176% | 5,688 |
| European (non-Finnish) | 0.0022% | 45,379 |

*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}

**KRT5** population constraint: LOEUF 0.538, pLI 0.90196, missense-Z 1.0035. *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 **87** lies in the 'head' region; a UniProt-annotated variant site (in ddd1).

AlphaFold model confidence (whole protein): pLDDT 68.86, 44% of residues very-high.

**2 experimental structure(s)** (PDB): [3TNU](https://www.rcsb.org/structure/3TNU), [6JFV](https://www.rcsb.org/structure/6JFV) — incl. mutant structure 6JFV.

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

*Describes the biological roles of KRT5 (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:** KRT5's established molecular role includes scaffold protein binding. p.Phe87Val falls in the head region.


### Pathways affected {#pathways}

KRT5 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Developmental Lineage of Mammary Gland Luminal Epithelial Cells](https://reactome.org/content/detail/R-HSA-9927418) | curated |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | curated |
| [Developmental Lineage of Mammary Stem Cells](https://reactome.org/content/detail/R-HSA-9938206) | curated |
| [Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin](https://reactome.org/content/detail/R-HSA-9725554) | curated |
| [Formation of the cornified envelope](https://reactome.org/content/detail/R-HSA-6809371) | curated |
| [Keratinization](https://reactome.org/content/detail/R-HSA-6805567) | curated |
| [Type I hemidesmosome assembly](https://reactome.org/content/detail/R-HSA-446107) | curated |

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

**Molecular function:** scaffold protein binding.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 6 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-04-24 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |

## Associated conditions {#conditions}

[epidermolysis bullosa simplex](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex/).

**Reported phenotype names (ClinVar):** Epidermolysis bullosa simplex, not provided, KRT5-related disorder, Uterine corpus endometrial carcinoma, Cholangiocarcinoma, KRT5-related condition, none provided, Epidermolysis bullosa simplex, Weber-Cockayne type (subtype), Epidermolysis bullosa simplex, Dowling-Meara type (subtype), Epidermolysis bullosa simplex with mottled pigmentation (subtype).

## Similar variants {#similar}

Related KRT5 variant pages (same residue, condition, or type): [KRT5 p.Phe87Cys](/variant/krt5-p-phe87cys), [KRT5 p.Phe87Leu](/variant/krt5-p-phe87leu), [KRT5 p.Ala428Thr](/variant/krt5-p-ala428thr), [KRT5 p.Ala428Val](/variant/krt5-p-ala428val), [KRT5 p.Glu170Lys](/variant/krt5-p-glu170lys), [KRT5 p.Glu466Gln](/variant/krt5-p-glu466gln), [KRT5 p.Glu477Lys](/variant/krt5-p-glu477lys), [KRT5 p.Leu196Pro](/variant/krt5-p-leu196pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 309571). 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.*