Is ATL2 p.Ile566Phe (c.1696A>T) pathogenic?

ATL2 p.Ile566Phe (c.1696A>T) is classified Uncertain significance in ATL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely benign (0.3062); Very rare (popmax 0.00273%, afr).

How common is ATL2 p.Ile566Phe (c.1696A>T) in the general population?

ATL2 p.Ile566Phe (c.1696A>T) is very rare (popmax 0.00273%, afr) (gnomAD).

What do computational predictors say about ATL2 p.Ile566Phe (c.1696A>T)?

AlphaMissense predicts likely benign (score 0.3062) — an in-silico prediction, not a clinical call.

ATL2 p.Ile566Phe

c.1696A>T · VCV4643971

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3062 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00273%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3062	likely benign
REVEL	0.374	indeterminate
SaProt	LLR -7.24	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 3.5	GERP 0.43, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 81 kb · p 0.18 · regional, not allelic
Overall
CADD	21.8	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 0.00273% African / African-American · 2/73,176 alleles

Filtering AF 0.000454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000143% 2/1,399,424 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: ATL2
Protein: p.Ile566Phe
Coding: c.1696A>T
MANE Select: NM_001135673
Type: single nucleotide variant
Location: chr2:38296050 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.36
Residue 566: the 'autoinhibitory domain' region

Full ATL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATL2 p.Gly365= Benign ★★ same type
ATL2 p.Ala100Val Uncertain significance ★ ⚠ same type
ATL2 p.Ala227Gly Uncertain significance ★ ⚠ same type
ATL2 p.Ala28Gly Uncertain significance ★ ⚠ same type
ATL2 p.Ala2Val Uncertain significance ★ ⚠ same type
ATL2 p.Ala388Ser Uncertain significance ★ ⚠ same type
ATL2 p.Ala388Val Uncertain significance ★ ⚠ same type
ATL2 p.Ala425Val 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/atl2-p-ile566phe (accessed [today's date]).

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