Is ACTL6B p.Leu52Pro (c.155T>C) pathogenic?

ACTL6B p.Leu52Pro (c.155T>C) is classified Uncertain significance in ACTL6B (ClinVar, Single submitter, 2 submitters; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0879); Very rare (popmax 0.000339%, nfe); Associated with intellectual developmental disorder with severe speech and ambulation defects.

What condition is associated with ACTL6B p.Leu52Pro (c.155T>C)?

ACTL6B p.Leu52Pro (c.155T>C) is associated with intellectual developmental disorder with severe speech and ambulation defects (ClinVar).

How common is ACTL6B p.Leu52Pro (c.155T>C) in the general population?

ACTL6B p.Leu52Pro (c.155T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ACTL6B p.Leu52Pro (c.155T>C)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

ACTL6B p.Leu52Pro

c.155T>C · rs1804023252 · VCV1710282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual developmental disorder with severe speech and ambulation defects

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.542	indeterminate
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 4.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 9,273 bp · p 1.9e-09 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,912 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,784 alleles · very rare

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.Leu52Pro
Coding: c.155T>C
MANE Select: NM_016188
dbSNP: rs1804023252
Type: single nucleotide variant
Location: chr7:100655534 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 52: the 'essential for mediating its function in dendritic development; may contribute to neuronal-specific targeting' region

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

Disease context

intellectual developmental disorder with severe speech and ambulation defects — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTL6B p.Arg97Ter Likely pathogenic ★★ same condition
ACTL6B p.Gly343Arg Pathogenic/Likely pathogenic ★★ same condition
ACTL6B p.Arg363Gln Uncertain significance ★★ ⚠ same condition
ACTL6B p.Val421Met Uncertain significance ★★ ⚠ same condition
ACTL6B c.*98T>A Benign ★★ same condition
ACTL6B p.Asn125Lys Likely pathogenic ★ same condition
ACTL6B p.Gly343Trp Likely pathogenic ★ same condition
ACTL6B p.Leu185Pro 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-leu52pro (accessed [today's date]).

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