Is ATL3 p.Ser458= (c.1374A>G) pathogenic?

ATL3 p.Ser458= (c.1374A>G) is classified Benign/Likely benign in ATL3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). Low-frequency (popmax 3.07%, afr); Associated with neuropathy, hereditary sensory, type 1F.

What condition is associated with ATL3 p.Ser458= (c.1374A>G)?

ATL3 p.Ser458= (c.1374A>G) is associated with neuropathy, hereditary sensory, type 1F (ClinVar).

How common is ATL3 p.Ser458= (c.1374A>G) in the general population?

ATL3 p.Ser458= (c.1374A>G) is low-frequency (popmax 3.07%, afr) (gnomAD).

ATL3 p.Ser458=

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.1374A>G · rs17158455 · VCV474832

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.07%, afr)

Conditions

neuropathy, hereditary sensory, type 1F

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -4.3
Overall
CADD	0.767	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.07% African / African-American · 2,308/75,060 alleles

Filtering AF 2.97% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.93%

Overall 0.158% 2,556/1,614,212 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.07%	33
Remaining individualsnot grpmax-eligible	0.184%	544
Admixed American	0.17%	588
Middle Eastern	0.099%	1,010
South Asian	0.00549%	18,217
European (non-Finnish)	0.00169%	59,002

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.Ser458=
Coding: c.1374A>G
MANE Select: NM_015459
dbSNP: rs17158455
Type: single nucleotide variant
Location: chr11:63631205 (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 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
ATL3 p.Ala540Ser 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-ser458 (accessed [today's date]).

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