Is ACTN4 p.Ala884= (c.2652G>A) pathogenic?

ACTN4 p.Ala884= (c.2652G>A) is classified Benign/Likely benign in ACTN4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-19). Ultra-rare (popmax 0.0254%, afr); Associated with focal segmental glomerulosclerosis 1.

What condition is associated with ACTN4 p.Ala884= (c.2652G>A)?

ACTN4 p.Ala884= (c.2652G>A) is associated with focal segmental glomerulosclerosis 1 (ClinVar).

How common is ACTN4 p.Ala884= (c.2652G>A) in the general population?

ACTN4 p.Ala884= (c.2652G>A) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

ACTN4 p.Ala884=

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.2652G>A · rs202127035 · VCV585363

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Conditions

focal segmental glomerulosclerosis 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -5.2
Overall
CADD	1.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% African / African-American · 19/74,902 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00998% 161/1,612,558 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
African / African-Americangrpmax	0.0254%	3,942
Admixed American	0.0217%	4,615
European (non-Finnish)	0.00873%	11,455
Remaining individualsnot grpmax-eligible	0.0064%	15,622
South Asian	0.0022%	45,533

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ACTN4
Protein: p.Ala884=
Coding: c.2652G>A
MANE Select: NM_004924
dbSNP: rs202127035
Type: single nucleotide variant
Location: chr19:38729348 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.66 · 5 PDB
Residue 884: the 'mediates interaction with micall2' 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.Ala884Val Uncertain significance ★ ⚠ 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
ACTN4 p.Ala784Val 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-ala884 (accessed [today's date]).

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