Is RETREG1 p.Ala2= (c.6G>A) pathogenic?

RETREG1 p.Ala2= (c.6G>A) is classified Uncertain significance in RETREG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.000183%, nfe); Associated with neuropathy, hereditary sensory and autonomic, type 2B.

What condition is associated with RETREG1 p.Ala2= (c.6G>A)?

RETREG1 p.Ala2= (c.6G>A) is associated with neuropathy, hereditary sensory and autonomic, type 2B (ClinVar).

How common is RETREG1 p.Ala2= (c.6G>A) in the general population?

RETREG1 p.Ala2= (c.6G>A) is very rare (popmax 0.000183%, nfe) (gnomAD).

RETREG1 p.Ala2=

Q: How is Hereditary sensory and autonomic neuropathy type 2 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.6G>A · rs750740230 · VCV352699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000183%, nfe)

Conditions

neuropathy, hereditary sensory and autonomic, type 2B

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 3.2	GERP 0.74, phastCons 1
Overall
CADD	16.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000183% European (non-Finnish) · 2/1,093,828 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00014% 2/1,429,166 alleles · very rare

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: RETREG1
Protein: p.Ala2=
Coding: c.6G>A
MANE Select: NM_001034850
dbSNP: rs750740230
Type: single nucleotide variant
Location: chr5:16616966 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 59.87 · 2 PDB
Residue 2: the 'disordered' region

Full RETREG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuropathy, hereditary sensory and autonomic, type 2B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary sensory and autonomic neuropathy type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RETREG1 p.Gln145Ter Pathogenic ★★ same condition
RETREG1 p.Ser309Ter Pathogenic ★★ same condition
RETREG1 c.808+6T>C Uncertain significance ★★ same condition
RETREG1 c.*1035T>C Uncertain significance ★★ same condition
RETREG1 p.Arg266Cys Uncertain significance ★★ ⚠ same condition
RETREG1 p.Arg268Thr Uncertain significance ★★ ⚠ same condition
RETREG1 p.Asp333Glu Uncertain significance ★★ ⚠ same condition
RETREG1 p.Cys170Ser 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/retreg1-p-ala2 (accessed [today's date]).

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