Is ANO4 p.Pro582Arg (c.1745C>G) pathogenic?

ANO4 p.Pro582Arg (c.1745C>G) is classified Uncertain significance in ANO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely pathogenic (0.9748); Very rare (popmax 0.000763%, nfe).

How common is ANO4 p.Pro582Arg (c.1745C>G) in the general population?

ANO4 p.Pro582Arg (c.1745C>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about ANO4 p.Pro582Arg (c.1745C>G)?

AlphaMissense predicts likely pathogenic (score 0.9748) — an in-silico prediction, not a clinical call.

ANO4 p.Pro582Arg

c.1745C>G · VCV4641185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9748	likely pathogenic
REVEL	0.42	indeterminate
SaProt	LLR -14.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 139 kb · p 1.7e-19 · regional, not allelic
Overall
CADD	28.9	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 0.000763% European (non-Finnish) · 9/1,179,344 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,206 alleles · very rare exomes 9/1,460,956 · genomes 0/152,250 · joint denominator

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: ANO4
Protein: p.Pro582Arg
Coding: c.1745C>G
MANE Select: NM_001286615
Type: single nucleotide variant
Location: chr12:101096542 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.27

Full ANO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANO4 p.Phe720Leu Uncertain significance ★★ ⚠ same type
ANO4 p.Val376Ile Likely benign ★★ same type
ANO4 p.Asn129Lys Pathogenic ★ ⚠ same type
ANO4 p.Asn558Lys Pathogenic ★ same type
ANO4 p.Asn603Asp Pathogenic ★ same type
ANO4 p.Ile562Phe Pathogenic ★ same type
ANO4 p.Met563Lys Pathogenic ★ same type
ANO4 p.Val528Met Pathogenic ★ ⚠ 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/ano4-p-pro582arg (accessed [today's date]).

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