Is ANO6 p.Arg648Ter (c.1942C>T) pathogenic?

ANO6 p.Arg648Ter (c.1942C>T) is classified Likely pathogenic in ANO6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). Very rare (popmax 0.00133%, afr).

How common is ANO6 p.Arg648Ter (c.1942C>T) in the general population?

ANO6 p.Arg648Ter (c.1942C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

ANO6 p.Arg648Ter

c.1942C>T · VCV3381086

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 20
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.61	GERP 1.7, phastCons 0.12
Overall
CADD	37.0	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 0.00133% African / African-American · 1/75,034 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000744% 12/1,613,980 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,034
South Asian	0.0011%	91,080
European (non-Finnish)	0.000848%	117,990

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: ANO6
Protein: p.Arg648Ter
Coding: c.1942C>T
MANE Select: NM_001025356
Type: single nucleotide variant
Location: chr12:45409418 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.00
Residue 648: a disulfide bond

Full ANO6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANO6 p.Arg648Leu Uncertain significance ★★ ⚠ same residue
ANO6 p.Arg648Gln Uncertain significance ★ ⚠ same residue
ANO6 c.1387-1G>T Pathogenic ★★ same type
ANO6 p.Arg253Cys Uncertain significance ★★ ⚠ same type
ANO6 p.Arg253His Uncertain significance ★★ ⚠ same type
ANO6 p.Arg276Gln Uncertain significance ★★ ⚠ same type
ANO6 p.Arg399Cys Uncertain significance ★★ same type
ANO6 p.Arg635Gln 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/ano6-p-arg648ter (accessed [today's date]).

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