Is ANO4 p.Phe370Ser (c.1109T>C) pathogenic?

ANO4 p.Phe370Ser (c.1109T>C) is classified Uncertain significance in ANO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: likely benign (0.3088); Very rare (popmax 0.00297%, nfe).

How common is ANO4 p.Phe370Ser (c.1109T>C) in the general population?

ANO4 p.Phe370Ser (c.1109T>C) is very rare (popmax 0.00297%, nfe) (gnomAD).

What do computational predictors say about ANO4 p.Phe370Ser (c.1109T>C)?

AlphaMissense predicts likely benign (score 0.3088) — an in-silico prediction, not a clinical call.

ANO4 p.Phe370Ser

c.1109T>C · VCV3400773

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3088 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3088	likely benign
REVEL	0.394	indeterminate
SaProt	LLR -8.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 139 kb · p 1.7e-19 · regional, not allelic
Overall
CADD	25.3	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 0.00297% European (non-Finnish) · 35/1,180,024 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00223% 36/1,614,036 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00297%	33,715
South Asian	0.0011%	91,084

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.Phe370Ser
Coding: c.1109T>C
MANE Select: NM_001286615
Type: single nucleotide variant
Location: chr12:101042423 (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-phe370ser (accessed [today's date]).

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