Is ATL3 p.Pro102Leu (c.305C>T) pathogenic?

ATL3 p.Pro102Leu (c.305C>T) is classified Uncertain significance in ATL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-22). AlphaMissense: ambiguous (0.3885); Very rare (popmax 0.00934%, afr); Associated with neuropathy, hereditary sensory, type 1F.

What condition is associated with ATL3 p.Pro102Leu (c.305C>T)?

ATL3 p.Pro102Leu (c.305C>T) is associated with neuropathy, hereditary sensory, type 1F (ClinVar).

How common is ATL3 p.Pro102Leu (c.305C>T) in the general population?

ATL3 p.Pro102Leu (c.305C>T) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about ATL3 p.Pro102Leu (c.305C>T)?

AlphaMissense predicts ambiguous (score 0.3885) — an in-silico prediction, not a clinical call.

ATL3 p.Pro102Leu

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.305C>T · rs574217792 · VCV1391353

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3885 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Conditions

neuropathy, hereditary sensory, type 1F

Computational evidence

Protein change
AlphaMissense	0.3885	ambiguous
REVEL	0.567	indeterminate
SaProt	LLR -11.86	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 42 kb · p 0.12 · regional, not allelic
Overall
CADD	26.2	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 0.00934% African / African-American · 7/74,908 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00149% 24/1,610,186 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,701
Admixed American	0.00336%	29,720
European (non-Finnish)	0.00119%	84,194
South Asian	0.00112%	89,614

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.Pro102Leu
Coding: c.305C>T
MANE Select: NM_015459
dbSNP: rs574217792
Type: single nucleotide variant
Location: chr11:63658861 (GRCh38)
Gene constraint: LOEUF 0.891 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.30 · 2 PDB
Residue 102: the gb1/rhd3-type g domain

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.Pro102= 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-pro102leu (accessed [today's date]).

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