Is ATL3 p.Ala540Ser (c.1618G>T) pathogenic?

ATL3 p.Ala540Ser (c.1618G>T) is classified Uncertain significance in ATL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-31). AlphaMissense: likely benign (0.0663); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with ATL3 p.Ala540Ser (c.1618G>T)?

ATL3 p.Ala540Ser (c.1618G>T) is associated with Inborn genetic diseases, neuropathy, hereditary sensory, type 1F (ClinVar).

How common is ATL3 p.Ala540Ser (c.1618G>T) in the general population?

ATL3 p.Ala540Ser (c.1618G>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about ATL3 p.Ala540Ser (c.1618G>T)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

ATL3 p.Ala540Ser

c.1618G>T · rs749790717 · VCV1776545

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -5.17	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 0.12	GERP -3.8, phastCons 0.048
Regional constraint	o/e 0.94	unconstrained · MANE · 42 kb · p 0.12 · regional, not allelic
Overall
CADD	1.777	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 0.0107% African / African-American · 8/74,874 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000496% 8/1,613,716 alleles · ultra-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: ATL3
Protein: p.Ala540Ser
Coding: c.1618G>T
MANE Select: NM_015459
dbSNP: rs749790717
Type: single nucleotide variant
Location: chr11:63629327 (GRCh38)
Gene constraint: LOEUF 0.891 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.30 · 2 PDB

Full ATL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuropathy, hereditary sensory, type 1F

Similar variants

ATL3 p.Ala540= Likely benign ★ same residue
ATL3 c.1035+1G>A Uncertain significance ★★ same condition
ATL3 c.46+1G>A Uncertain significance ★★ same condition
ATL3 c.619-4A>G Uncertain significance ★★ same condition
ATL3 c.711+1G>T Uncertain significance ★★ same condition
ATL3 c.850+5G>A Uncertain significance ★★ same condition
ATL3 p.Ala457Val Uncertain significance ★★ ⚠ same condition
ATL3 p.Ala508Thr Uncertain significance ★★ ⚠ same condition

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/atl3-p-ala540ser (accessed [today's date]).

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