Is ACTL6B p.Pro232fs (c.695del) pathogenic?

ACTL6B p.Pro232fs (c.695del) is classified Conflicting classifications of pathogenicity in ACTL6B (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-03-22). Very rare (popmax 0.00445%, sas); Associated with developmental and epileptic encephalopathy, 76.

What condition is associated with ACTL6B p.Pro232fs (c.695del)?

ACTL6B p.Pro232fs (c.695del) is associated with developmental and epileptic encephalopathy, 76 (ClinVar).

How common is ACTL6B p.Pro232fs (c.695del) in the general population?

ACTL6B p.Pro232fs (c.695del) is very rare (popmax 0.00445%, sas) (gnomAD).

ACTL6B p.Pro232fs

c.695del · rs779550102 · VCV828180

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00445%, sas)

Conditions

developmental and epileptic encephalopathy, 76

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.15	GERP -1.4, phastCons 0.98
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% South Asian · 4/89,886 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.000808% 13/1,608,302 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00445%	22,472
Admixed American	0.00168%	59,556
Remaining individualsnot grpmax-eligible	0.00161%	62,286
European (non-Finnish)	0.000595%	168,160

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: ACTL6B
Protein: p.Pro232fs
Coding: c.695del
MANE Select: NM_016188
dbSNP: rs779550102
Type: Deletion
Location: chr7:100647508 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 232: a UniProt-annotated variant site (in dee76)

Full ACTL6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 76 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTL6B p.Pro232Arg Uncertain significance ★★ ⚠ same residue
ACTL6B p.Gly50fs Pathogenic/Likely pathogenic ★★ same condition
ACTL6B p.Ser409fs Likely pathogenic ★ same condition
ACTL6B p.Asp77fs Uncertain significance ★ same condition
ACTL6B p.Pro232Thr Uncertain significance ★ same residue
ACTL6B p.Met210fs Pathogenic same condition
ACTL6B p.Ter427AspextTer? Pathogenic/Likely pathogenic same condition
ACTL6B p.Arg97Ter Likely pathogenic ★★ 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/actl6b-p-pro232fs (accessed [today's date]).

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