Is SPTLC2 p.Pro476= (c.1428T>G) pathogenic?

SPTLC2 p.Pro476= (c.1428T>G) is classified Benign in SPTLC2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). Low-frequency (popmax 4.13%, afr); Associated with neuropathy, hereditary sensory and autonomic, type 1C.

What condition is associated with SPTLC2 p.Pro476= (c.1428T>G)?

SPTLC2 p.Pro476= (c.1428T>G) is associated with neuropathy, hereditary sensory and autonomic, type 1C (ClinVar).

How common is SPTLC2 p.Pro476= (c.1428T>G) in the general population?

SPTLC2 p.Pro476= (c.1428T>G) is low-frequency (popmax 4.13%, afr) (gnomAD).

SPTLC2 p.Pro476=

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.1428T>G · rs34418677 · VCV314668

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.13%, afr)

Conditions

neuropathy, hereditary sensory and autonomic, type 1C

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 -1.7	GERP -4.5
Overall
CADD	2.695	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.13% African / African-American · 3,100/75,040 alleles

Filtering AF 4.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.96%

Overall 0.215% 3,467/1,614,188 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.13%	24
Remaining individualsnot grpmax-eligible	0.28%	357
Middle Eastern	0.264%	379
Admixed American	0.185%	541
South Asian	0.00769%	13,012
European (non-Finnish)	0.00492%	20,346

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: SPTLC2
Protein: p.Pro476=
Coding: c.1428T>G
MANE Select: NM_004863
dbSNP: rs34418677
Type: single nucleotide variant
Location: chr14:77521457 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.47 · 17 PDB
Residue 476: an α-helix

Full SPTLC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuropathy, hereditary sensory and autonomic, type 1C — 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

SPTLC2 p.Arg183Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
SPTLC2 p.Gly382Val Pathogenic/Likely pathogenic ★★ same condition
SPTLC2 p.Ser384Phe Pathogenic/Likely pathogenic ★★ ⚠ same condition
SPTLC2 c.1176+6C>T Uncertain significance ★★ same condition
SPTLC2 c.756+3A>G Uncertain significance ★★ same condition
SPTLC2 c.-160A>G Uncertain significance ★★ same condition
SPTLC2 c.*100G>A Uncertain significance ★★ same condition
SPTLC2 p.Ala231Thr 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/sptlc2-p-pro476 (accessed [today's date]).

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