Is ANO3 p.Arg253Lys (c.758G>A) pathogenic?

ANO3 p.Arg253Lys (c.758G>A) is classified Uncertain significance in ANO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-23). AlphaMissense: likely benign (0.0698); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ANO3 p.Arg253Lys (c.758G>A)?

ANO3 p.Arg253Lys (c.758G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ANO3 p.Arg253Lys (c.758G>A) in the general population?

ANO3 p.Arg253Lys (c.758G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ANO3 p.Arg253Lys (c.758G>A)?

AlphaMissense predicts likely benign (score 0.0698) — an in-silico prediction, not a clinical call.

ANO3 p.Arg253Lys

c.758G>A · VCV3874940

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0698	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -5.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	acceptor loss, 20 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.6	GERP 0.62, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 5,668 bp · p 0.084 · regional, not allelic
Overall
CADD	20.9	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 8.47e-05% European (non-Finnish) · 1/1,179,962 alleles

Overall 6.84e-05% 1/1,461,696 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: ANO3
Protein: p.Arg253Lys
Coding: c.758G>A
MANE Select: NM_031418
Type: single nucleotide variant
Location: chr11:26531225 (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

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

Similar variants

ANO3 p.Ile607Phe Pathogenic/Likely pathogenic ★★ same condition
ANO3 p.Ala41Ser Uncertain significance ★★ ⚠ same condition
ANO3 p.Ala41Thr Uncertain significance ★★ ⚠ same condition
ANO3 p.Arg125His Uncertain significance ★★ ⚠ same condition
ANO3 p.Arg305Gln Uncertain significance ★★ ⚠ same condition
ANO3 p.Arg34Gln Uncertain significance ★★ ⚠ same condition
ANO3 p.Arg368Cys Uncertain significance ★★ ⚠ same condition
ANO3 p.Arg969Trp 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-arg253lys (accessed [today's date]).

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