# NM_004924.6(ACTN4):c.458T>C (p.Phe153Ser)

https://sugi.bio/variant/actn4-p-phe153ser

## Summary

**ACTN4 p.Phe153Ser (c.458T>C)** is classified **Likely pathogenic** in ACTN4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-05-17). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with focal segmental glomerulosclerosis 1.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs1568723797 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ACTN4 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to focal segmental glomerulosclerosis 1.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Diagnostic panels | ACTN4 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Hereditary steroid-resistant nephrotic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Proteinuria — Obligate (100%)
- Edema — Very frequent (99-80%)
- Focal segmental glomerulosclerosis — Frequent (79-30%)
- Stage 5 chronic kidney disease — Frequent (79-30%)
- Chronic kidney disease — Frequent (79-30%)
- Periorbital edema — Frequent (79-30%)
- Irritability — Occasional (29-5%)
- Fever — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015353/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACTN4](https://sugi.bio/atlas/gene/ACTN4/) |
| Protein change (HGVS p.) | p.Phe153Ser |
| Coding change (HGVS c.) | c.458T>C |
| MANE Select transcript | [NM_004924](https://www.ncbi.nlm.nih.gov/nuccore/NM_004924) |
| dbSNP | [rs1568723797](https://www.ncbi.nlm.nih.gov/snp/rs1568723797/) |
| Variant type | single nucleotide variant |
| Location | chr19:38704994-38704994 (GRCh38) |
| ClinVar | [VCV599130](https://www.ncbi.nlm.nih.gov/clinvar/variation/599130/) |

**All HGVS expressions:** `NC_000019.10:g.38704994T>C`, `NC_000019.9:g.39195634T>C`, `NG_007082.2:g.62308T>C`, `NM_001322033.2:c.458T>C`, `NM_004924.6:c.458T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9999) — concordant with the pathogenic call
- REVEL 0.967 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.465 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.925, GERP 2.58, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in ACTN4 (of 5,475 modeled).
- CADD: **PHRED 28.6**. 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 0.41** across the covering region of the MANE Select transcript (38,647,904–38,714,511), spanning 66,607 bp. Chi-square p 1.5e-25. 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). 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. This allele is not in the release, so all four of its deltas are under 0.2. 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, and here that is proven rather than inferred: a different substitution at this very position, T>A, IS in the release and scores Δ0.64 donor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ACTN4** population constraint: LOEUF 0.238, pLI 1, missense-Z 5.6941. *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 **153** lies in the calponin-homology (ch) 1 domain; a UniProt-annotated variant site (in fsgs1; uncertain significance); an α-helix; the 'actin-binding' region.

AlphaFold model confidence (whole protein): pLDDT 84.66, 48% of residues very-high.

**5 experimental structure(s)** (PDB): [1WLX](https://www.rcsb.org/structure/1WLX), [1YDI](https://www.rcsb.org/structure/1YDI), [2R0O](https://www.rcsb.org/structure/2R0O), [6O31](https://www.rcsb.org/structure/6O31), [6OA6](https://www.rcsb.org/structure/6OA6) — incl. mutant structure 2R0O.

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

*Describes the biological roles of ACTN4 (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:** ACTN4's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Phe153Ser falls in the calponin-homology (ch) 1 domain.


### Pathways affected {#pathways}

ACTN4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Nephrin family interactions](https://reactome.org/content/detail/R-HSA-373753) | electronic |

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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, nucleoside binding, transcription coactivator activity, RNA binding, nuclear receptor binding, chromatin DNA binding.

**Biological process:** vesicle transport along actin filament, positive regulation of cell migration, tumor necrosis factor-mediated signaling pathway, peroxisome proliferator activated receptor signaling pathway, positive regulation of transcription by RNA polymerase II, retinoic acid receptor signaling pathway.

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2018-05-17.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Likely pathogenic | no assertion criteria provided | clinical testing | 2018-05-17 |

## Associated conditions {#conditions}

[focal segmental glomerulosclerosis 1](https://sugi.bio/atlas/disease/focal-segmental-glomerulosclerosis-1/).

**Reported phenotype names (ClinVar):** Focal segmental glomerulosclerosis 1.

## Similar variants {#similar}

Related ACTN4 variant pages (same residue, condition, or type): [ACTN4 p.Phe153Leu](/variant/actn4-p-phe153leu), [ACTN4 p.Phe153=](/variant/actn4-p-phe153), [ACTN4 p.Lys255Glu](/variant/actn4-p-lys255glu), [ACTN4 c.1443-7C>T](/variant/actn4-c-1443-minus-7c-t), [ACTN4 c.2190+5G>A](/variant/actn4-c-2190-plus-5g-a), [ACTN4 c.2190+6C>T](/variant/actn4-c-2190-plus-6c-t), [ACTN4 p.Ala475Thr](/variant/actn4-p-ala475thr), [ACTN4 p.Ala759Thr](/variant/actn4-p-ala759thr).

### 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 599130). 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.*