Is ATL3 p.Phe438Ile (c.1312T>A) pathogenic?

ATL3 p.Phe438Ile (c.1312T>A) is classified Uncertain significance in ATL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely pathogenic (0.8765); Very rare (popmax 0.0011%, nfe); Associated with neuropathy, hereditary sensory, type 1F.

What condition is associated with ATL3 p.Phe438Ile (c.1312T>A)?

ATL3 p.Phe438Ile (c.1312T>A) is associated with neuropathy, hereditary sensory, type 1F (ClinVar).

How common is ATL3 p.Phe438Ile (c.1312T>A) in the general population?

ATL3 p.Phe438Ile (c.1312T>A) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about ATL3 p.Phe438Ile (c.1312T>A)?

AlphaMissense predicts likely pathogenic (score 0.8765) — an in-silico prediction, not a clinical call.

ATL3 p.Phe438Ile

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.1312T>A · rs964472038 · VCV1024318

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuropathy, hereditary sensory, type 1F

Computational evidence

Protein change
AlphaMissense	0.8765	likely pathogenic
REVEL	0.927	moderately pathogenic-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 42 kb · p 0.12 · regional, not allelic
Overall
CADD	27.5	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 0.0011% European (non-Finnish) · 13/1,180,042 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000958% 14/1,461,892 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	0.0011%	90,772

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe438Ile
Coding: c.1312T>A
MANE Select: NM_015459
dbSNP: rs964472038
Type: single nucleotide variant
Location: chr11:63631267 (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

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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
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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-phe438ile (accessed [today's date]).

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