Is ATL3 p.Arg235Cys (c.703C>T) pathogenic?

ATL3 p.Arg235Cys (c.703C>T) is classified Uncertain significance in ATL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-28). AlphaMissense: likely pathogenic (0.7705); Very rare (popmax 0.00111%, sas); Associated with neuropathy, hereditary sensory, type 1F.

What condition is associated with ATL3 p.Arg235Cys (c.703C>T)?

ATL3 p.Arg235Cys (c.703C>T) is associated with neuropathy, hereditary sensory, type 1F (ClinVar).

How common is ATL3 p.Arg235Cys (c.703C>T) in the general population?

ATL3 p.Arg235Cys (c.703C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about ATL3 p.Arg235Cys (c.703C>T)?

AlphaMissense predicts likely pathogenic (score 0.7705) — an in-silico prediction, not a clinical call.

ATL3 p.Arg235Cys

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.703C>T · rs913464202 · VCV541679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuropathy, hereditary sensory, type 1F

Computational evidence

Protein change
AlphaMissense	0.7705	likely pathogenic
REVEL	0.394	indeterminate
SaProt	LLR -13.06	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 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 42 kb · p 0.12 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00111% South Asian · 1/89,814 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000437% 7/1,602,136 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	89,814
European (non-Finnish)	0.000512%	195,286

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.Arg235Cys
Coding: c.703C>T
MANE Select: NM_015459
dbSNP: rs913464202
Type: single nucleotide variant
Location: chr11:63644177 (GRCh38)
Gene constraint: LOEUF 0.891 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.30 · 2 PDB
Residue 235: an α-helix; 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

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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-arg235cys (accessed [today's date]).

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