Is ACTL6B p.Thr69= (c.207C>G) pathogenic?

ACTL6B p.Thr69= (c.207C>G) is classified Likely benign in ACTL6B (ClinVar, Single submitter, 2 submitters; last evaluated 2024-09-06). Ultra-rare (popmax 0.0164%, mid).

How common is ACTL6B p.Thr69= (c.207C>G) in the general population?

ACTL6B p.Thr69= (c.207C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

ACTL6B p.Thr69=

c.207C>G · rs367833321 · VCV3049544

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 8.5	GERP 2.7, phastCons 1
Overall
CADD	12.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0129% 209/1,614,064 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,935
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.0163%	6,146
Remaining individualsnot grpmax-eligible	0.0112%	8,926
Admixed American	0.00333%	30,000
Finnishnot grpmax-eligible	0.00156%	64,034

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: ACTL6B
Protein: p.Thr69=
Coding: c.207C>G
MANE Select: NM_016188
dbSNP: rs367833321
Type: single nucleotide variant
Location: chr7:100655482 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 69: 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

Similar variants

ACTL6B p.Arg97Ter Likely pathogenic ★★ same type
ACTL6B p.Gln186Ter Pathogenic/Likely pathogenic ★★ same type
ACTL6B p.Gln278Ter Likely pathogenic ★★ same type
ACTL6B p.Gly343Arg Pathogenic/Likely pathogenic ★★ same type
ACTL6B p.Gly349Ser Likely pathogenic ★★ same type
ACTL6B p.Trp247Ter Likely pathogenic ★★ same type
ACTL6B p.Arg363Gln Uncertain significance ★★ ⚠ same type
ACTL6B p.Glu297Lys Uncertain significance ★★ ⚠ same type

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-thr69 (accessed [today's date]).

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