Is ATL3 p.Ala508Pro (c.1522G>C) pathogenic?

ATL3 p.Ala508Pro (c.1522G>C) is classified Uncertain significance in ATL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: likely pathogenic (0.9398); Absent from gnomAD v4.1; Associated with neuropathy, hereditary sensory, type 1F.

What condition is associated with ATL3 p.Ala508Pro (c.1522G>C)?

ATL3 p.Ala508Pro (c.1522G>C) is associated with neuropathy, hereditary sensory, type 1F (ClinVar).

How common is ATL3 p.Ala508Pro (c.1522G>C) in the general population?

ATL3 p.Ala508Pro (c.1522G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATL3 p.Ala508Pro (c.1522G>C)?

AlphaMissense predicts likely pathogenic (score 0.9398) — an in-silico prediction, not a clinical call.

ATL3 p.Ala508Pro

Q: How is Hereditary sensory and autonomic neuropathy type 1 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1522G>C · VCV3669667

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9398 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuropathy, hereditary sensory, type 1F

Computational evidence

Protein change
AlphaMissense	0.9398	likely pathogenic
REVEL	0.434	indeterminate
SaProt	LLR -13.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.13, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 42 kb · p 0.12 · regional, not allelic
Overall
CADD	17.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ATL3
Protein: p.Ala508Pro
Coding: c.1522G>C
MANE Select: NM_015459
Type: single nucleotide variant
Location: chr11:63631057 (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

neuropathy, hereditary sensory, type 1F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary sensory and autonomic neuropathy type 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

ATL3 p.Ala508Thr Uncertain significance ★★ ⚠ same residue
ATL3 p.Ala508= Likely benign ★ same residue
ATL3 p.Ala508Val Uncertain significance ★ ⚠ 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

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-ala508pro (accessed [today's date]).

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