Is ATL3 p.Arg442Ter (c.1324C>T) pathogenic?

ATL3 p.Arg442Ter (c.1324C>T) is classified Conflicting classifications of pathogenicity in ATL3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-11-24). Ultra-rare (popmax 0.033%, mid); Associated with neuropathy, hereditary sensory, type 1F.

What condition is associated with ATL3 p.Arg442Ter (c.1324C>T)?

ATL3 p.Arg442Ter (c.1324C>T) is associated with neuropathy, hereditary sensory, type 1F (ClinVar).

How common is ATL3 p.Arg442Ter (c.1324C>T) in the general population?

ATL3 p.Arg442Ter (c.1324C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

ATL3 p.Arg442Ter

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.1324C>T · rs767929561 · VCV1769970

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

neuropathy, hereditary sensory, type 1F

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.3, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00335% 49/1,461,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
South Asian	0.0165%	6,072
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00254%	39,334
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Arg442Ter
Coding: c.1324C>T
MANE Select: NM_015459
dbSNP: rs767929561
Type: single nucleotide variant
Location: chr11:63631255 (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.Arg442Gln 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
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-arg442ter (accessed [today's date]).

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