Is ANO4 p.Ile562Phe (c.1684A>T) pathogenic?

ANO4 p.Ile562Phe (c.1684A>T) is classified Pathogenic in ANO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9521); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy.

What condition is associated with ANO4 p.Ile562Phe (c.1684A>T)?

ANO4 p.Ile562Phe (c.1684A>T) is associated with developmental and epileptic encephalopathy (ClinVar).

How common is ANO4 p.Ile562Phe (c.1684A>T) in the general population?

ANO4 p.Ile562Phe (c.1684A>T) is absent from gnomAD v4.1 (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ANO4 p.Ile562Phe (c.1684A>T)?

AlphaMissense predicts likely pathogenic (score 0.9521) — an in-silico prediction, not a clinical call.

ANO4 p.Ile562Phe

c.1684A>T · rs2049521857 · VCV3067133

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9521 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy

Computational evidence

Protein change
AlphaMissense	0.9521	likely pathogenic ✓ concordant with ClinVar
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -14.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 139 kb · p 1.7e-19 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANO4
Protein: p.Ile562Phe
Coding: c.1684A>T
MANE Select: NM_001286615
dbSNP: rs2049521857
Type: single nucleotide variant
Location: chr12:101086807 (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

Disease context

developmental and epileptic encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

ANO4 p.Asn129Lys Pathogenic ★ ⚠ same condition
ANO4 p.Asn558Lys Pathogenic ★ same condition
ANO4 p.Asn603Asp Pathogenic ★ same condition
ANO4 p.Met563Lys Pathogenic ★ same condition
ANO4 p.Arg448Trp Uncertain significance ★ ⚠ same condition
ANO4 p.Phe720Leu Uncertain significance ★★ ⚠ same type
ANO4 p.Val376Ile Likely benign ★★ 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-ile562phe (accessed [today's date]).

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