Is ACTL6A p.Asp339= (c.1017C>T) pathogenic?

ACTL6A p.Asp339= (c.1017C>T) is classified Benign in ACTL6A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-04-21). Common (popmax 89.9%, eas) — too common for a highly-penetrant pathogenic allele.

ACTL6A p.Asp339=

Q: How common is ACTL6A p.Asp339= (c.1017C>T) in the general population?

ACTL6A p.Asp339= (c.1017C>T) is common (popmax 89.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1017C>T · rs1132429 · VCV1263459

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 89.9%, eas) — too common for a highly-penetrant pathogenic allele

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 -0.83	GERP -4.4, phastCons 0.009
Overall
CADD	6.014	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 89.9% East Asian · 40,334/44,860 alleles

Filtering AF 89.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 88.9%

Overall 63.5% 1,023,152/1,610,988 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	89.9%	1
Amishnot grpmax-eligible	74%	1
Ashkenazi Jewishnot grpmax-eligible	70.3%	1
South Asian	69.9%	1
Middle Eastern	66%	2
Remaining individualsnot grpmax-eligible	64.8%	2
Admixed American	64.4%	2
European (non-Finnish)	62.4%	2
Finnishnot grpmax-eligible	62.2%	2
African / African-American	54.4%	2

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: ACTL6A
Protein: p.Asp339=
Coding: c.1017C>T
MANE Select: NM_004301
dbSNP: rs1132429
Type: single nucleotide variant
Location: chr3:179581211 (GRCh38)
Gene constraint: LOEUF 0.186 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.04 · 31 PDB
Residue 339: a turn

Full ACTL6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTL6A p.Arg389Trp Uncertain significance ★★ ⚠ same type
ACTL6A p.Arg390Ser Uncertain significance ★★ ⚠ same type
ACTL6A c.1209+1G>C Uncertain significance ★ same type
ACTL6A c.477-1G>C Uncertain significance ★ same type
ACTL6A c.477-2A>G Uncertain significance ★ same type
ACTL6A c.572-4A>G Uncertain significance ★ same type
ACTL6A c.768+1G>A Uncertain significance ★ same type
ACTL6A p.Ala28Thr 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/actl6a-p-asp339 (accessed [today's date]).

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