Is ACTN4 p.Phe153Ser (c.458T>C) pathogenic?

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.

What condition is associated with ACTN4 p.Phe153Ser (c.458T>C)?

ACTN4 p.Phe153Ser (c.458T>C) is associated with focal segmental glomerulosclerosis 1 (ClinVar).

How common is ACTN4 p.Phe153Ser (c.458T>C) in the general population?

ACTN4 p.Phe153Ser (c.458T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN4 p.Phe153Ser (c.458T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

ACTN4 p.Phe153Ser

Q: How is Hereditary steroid-resistant nephrotic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.458T>C · rs1568723797 · VCV599130

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

focal segmental glomerulosclerosis 1

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 3% in ACTN4
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -15.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.64 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 67 kb · p 1.5e-25 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTN4
Protein: p.Phe153Ser
Coding: c.458T>C
MANE Select: NM_004924
dbSNP: rs1568723797
Type: single nucleotide variant
Location: chr19:38704994 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.66 · 5 PDB
Residue 153: the calponin-homology (ch) 1 domain; a UniProt-annotated variant site (in fsgs1; uncertain significance); an α-helix; the 'actin-binding' region

Full ACTN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

focal segmental glomerulosclerosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary steroid-resistant nephrotic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal

Similar variants

ACTN4 p.Phe153Leu Uncertain significance ★ ⚠ same residue
ACTN4 p.Phe153= Likely benign ★ same residue
ACTN4 p.Lys255Glu Pathogenic ★★ same condition
ACTN4 c.1443-7C>T Uncertain significance ★★ same condition
ACTN4 c.2190+5G>A Uncertain significance ★★ same condition
ACTN4 c.2190+6C>T Uncertain significance ★★ same condition
ACTN4 p.Ala475Thr Uncertain significance ★★ ⚠ same condition
ACTN4 p.Ala759Thr Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/actn4-p-phe153ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown