Is ACTN4 p.Pro99= (c.297G>A) pathogenic?

ACTN4 p.Pro99= (c.297G>A) is classified Benign/Likely benign in ACTN4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-17). Rare (popmax 0.155%, afr); Associated with Inborn genetic diseases.

What condition is associated with ACTN4 p.Pro99= (c.297G>A)?

ACTN4 p.Pro99= (c.297G>A) is associated with Inborn genetic diseases, focal segmental glomerulosclerosis 1 (ClinVar).

How common is ACTN4 p.Pro99= (c.297G>A) in the general population?

ACTN4 p.Pro99= (c.297G>A) is rare (popmax 0.155%, afr) (gnomAD).

ACTN4 p.Pro99=

c.297G>A · rs144919593 · VCV1169705

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.155%, afr)

Conditions

Inborn genetic diseases

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	0.493	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.155% African / African-American · 116/75,032 alleles

Filtering AF 0.132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.00967% 156/1,614,006 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.155%	647
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Admixed American	0.0167%	6,002
Finnishnot grpmax-eligible	0.00469%	21,326
South Asian	0.00329%	30,360
European (non-Finnish)	0.0011%	90,771

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.Pro99=
Coding: c.297G>A
MANE Select: NM_004924
dbSNP: rs144919593
Type: single nucleotide variant
Location: chr19:38701021 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.66 · 5 PDB
Residue 99: the calponin-homology (ch) 1 domain; an α-helix; the 'actin-binding' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: focal segmental glomerulosclerosis 1

Similar variants

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
ACTN4 p.Ala881Thr 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-pro99 (accessed [today's date]).

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