Is ANO6 p.Asp58Glu (c.174C>G) pathogenic?

ANO6 p.Asp58Glu (c.174C>G) is classified Uncertain significance in ANO6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely benign (0.2157); Very rare (popmax 8.49e-05%, nfe).

How common is ANO6 p.Asp58Glu (c.174C>G) in the general population?

ANO6 p.Asp58Glu (c.174C>G) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about ANO6 p.Asp58Glu (c.174C>G)?

AlphaMissense predicts likely benign (score 0.2157) — an in-silico prediction, not a clinical call.

ANO6 p.Asp58Glu

c.174C>G · rs2547450729 · VCV2072800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2157 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2157	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -5.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -0.99, phastCons 0.99
Regional constraint	o/e 0.85	unconstrained · MANE · 213 kb · p 7e-07 · regional, not allelic
Overall
CADD	18.56	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.49e-05% European (non-Finnish) · 1/1,177,628 alleles

Overall 6.86e-05% 1/1,457,498 alleles · very rare

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.Asp58Glu
Coding: c.174C>G
MANE Select: NM_001025356
dbSNP: rs2547450729
Type: single nucleotide variant
Location: chr12:45331318 (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

Similar variants

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
ANO6 p.Arg648Leu Uncertain significance ★★ ⚠ same type
ANO6 p.Arg862Cys 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-asp58glu (accessed [today's date]).

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