Is ANO6 p.Leu247Phe (c.739C>T) pathogenic?

ANO6 p.Leu247Phe (c.739C>T) is classified Uncertain significance in ANO6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely pathogenic (0.8653); Ultra-rare (popmax 0.0156%, eas); Associated with Inborn genetic diseases.

What condition is associated with ANO6 p.Leu247Phe (c.739C>T)?

ANO6 p.Leu247Phe (c.739C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ANO6 p.Leu247Phe (c.739C>T) in the general population?

ANO6 p.Leu247Phe (c.739C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about ANO6 p.Leu247Phe (c.739C>T)?

AlphaMissense predicts likely pathogenic (score 0.8653) — an in-silico prediction, not a clinical call.

ANO6 p.Leu247Phe

c.739C>T · VCV3919501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8653 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8653	likely pathogenic
REVEL	0.544	indeterminate
SaProt	LLR -12.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 213 kb · p 7e-07 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0156% East Asian · 7/44,862 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000558% 9/1,612,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,409
European (non-Finnish)	0.00017%	589,539

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.Leu247Phe
Coding: c.739C>T
MANE Select: NM_001025356
Type: single nucleotide variant
Location: chr12:45348623 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.00

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANO6 p.Arg253Cys Uncertain significance ★★ ⚠ same condition
ANO6 p.Arg253His Uncertain significance ★★ ⚠ same condition
ANO6 p.Arg276Gln Uncertain significance ★★ ⚠ same condition
ANO6 p.Arg399Cys Uncertain significance ★★ ⚠ same condition
ANO6 p.Arg635Gln Uncertain significance ★★ ⚠ same condition
ANO6 p.Arg648Leu Uncertain significance ★★ ⚠ same condition
ANO6 p.Arg862Cys Uncertain significance ★★ ⚠ same condition
ANO6 p.Arg896Gln 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/ano6-p-leu247phe (accessed [today's date]).

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