Is ANO3 p.Phe663= (c.1989C>T) pathogenic?

ANO3 p.Phe663= (c.1989C>T) is classified Benign in ANO3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 47.7%, sas) — too common for a highly-penetrant pathogenic allele; Associated with dystonic disorder.

What condition is associated with ANO3 p.Phe663= (c.1989C>T)?

ANO3 p.Phe663= (c.1989C>T) is associated with dystonic disorder, dystonia 24 (ClinVar).

ANO3 p.Phe663=

Q: How common is ANO3 p.Phe663= (c.1989C>T) in the general population?

ANO3 p.Phe663= (c.1989C>T) is common (popmax 47.7%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1989C>T · rs7946841 · VCV1166341

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 47.7%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

dystonic disorder

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 0.48	GERP -3.9, phastCons 1
Overall
CADD	10.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 47.7% South Asian · 43,343/90,856 alleles

Filtering AF 47.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 47.2%

Overall 39.8% 641,106/1,610,024 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	47.7%	2
Ashkenazi Jewishnot grpmax-eligible	43.1%	2
European (non-Finnish)	41.5%	2
Middle Eastern	39.5%	3
Remaining individualsnot grpmax-eligible	38.5%	3
East Asian	37%	3
Amishnot grpmax-eligible	36%	3
Finnishnot grpmax-eligible	34.2%	3
Admixed American	25.1%	4
African / African-American	22.7%	4

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: ANO3
Protein: p.Phe663=
Coding: c.1989C>T
MANE Select: NM_031418
dbSNP: rs7946841
Type: single nucleotide variant
Location: chr11:26635016 (GRCh38)
Gene constraint: LOEUF 0.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.30

Full ANO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dystonic disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dystonia 24

Similar variants

ANO3 p.Ala657Thr Likely pathogenic ★★ same condition
ANO3 p.Asn648Ser Pathogenic/Likely pathogenic ★★ same condition
ANO3 p.Glu510Lys Pathogenic/Likely pathogenic ★★ same condition
ANO3 p.Gly567Arg Likely pathogenic ★★ same condition
ANO3 p.Ile607Phe Pathogenic/Likely pathogenic ★★ same condition
ANO3 c.1836+4A>C Uncertain significance ★★ same condition
ANO3 c.2141+1G>A Uncertain significance ★★ same condition
ANO3 c.2276-6T>C 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/ano3-p-phe663 (accessed [today's date]).

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