Is ANO4 p.Ile243Phe (c.727A>T) pathogenic?

ANO4 p.Ile243Phe (c.727A>T) is classified Uncertain significance in ANO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). AlphaMissense: ambiguous (0.4251); Very rare (popmax 0.00446%, eas).

How common is ANO4 p.Ile243Phe (c.727A>T) in the general population?

ANO4 p.Ile243Phe (c.727A>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ANO4 p.Ile243Phe (c.727A>T)?

AlphaMissense predicts ambiguous (score 0.4251) — an in-silico prediction, not a clinical call.

ANO4 p.Ile243Phe

c.727A>T · VCV3298809

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4251 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4251	ambiguous
REVEL	0.221	benign-leaning
SaProt	LLR -8.22	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.26	donor loss · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 139 kb · p 1.7e-19 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 0.00446% East Asian · 2/44,890 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,824 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: ANO4
Protein: p.Ile243Phe
Coding: c.727A>T
MANE Select: NM_001286615
Type: single nucleotide variant
Location: chr12:100987663 (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-ile243phe (accessed [today's date]).

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