Is ANO4 p.Val376Ile (c.1126G>A) pathogenic?

ANO4 p.Val376Ile (c.1126G>A) is classified Likely benign in ANO4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-10). AlphaMissense: likely benign (0.0678); Rare (popmax 0.609%, nfe).

How common is ANO4 p.Val376Ile (c.1126G>A) in the general population?

ANO4 p.Val376Ile (c.1126G>A) is rare (popmax 0.609%, nfe) (gnomAD).

What do computational predictors say about ANO4 p.Val376Ile (c.1126G>A)?

AlphaMissense predicts likely benign (score 0.0678) — an in-silico prediction, not a clinical call.

ANO4 p.Val376Ile

c.1126G>A · rs116925463 · VCV778657

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0678 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.609%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0678	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -5.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.15, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 139 kb · p 1.7e-19 · regional, not allelic
Overall
CADD	15.79	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 0.609% European (non-Finnish) · 7,187/1,179,992 alleles

Filtering AF 0.597% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.592%

Overall 0.484% 7,820/1,614,056 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.609%	164
Remaining individualsnot grpmax-eligible	0.363%	275
Admixed American	0.275%	364
Ashkenazi Jewishnot grpmax-eligible	0.257%	390
Middle Eastern	0.231%	433
African / African-American	0.0893%	1,120
South Asian	0.0769%	1,301
Finnishnot grpmax-eligible	0.0203%	4,925
East Asian	0.00223%	44,876

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.Val376Ile
Coding: c.1126G>A
MANE Select: NM_001286615
dbSNP: rs116925463
Type: single nucleotide variant
Location: chr12:101042440 (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.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
ANO4 p.Ala416Gly Uncertain significance ★ ⚠ 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-val376ile (accessed [today's date]).

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