Is SPTLC2 p.Pro5Ser (c.13C>T) pathogenic?

SPTLC2 p.Pro5Ser (c.13C>T) is classified Uncertain significance in SPTLC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-04). AlphaMissense: likely benign (0.0746); Very rare (popmax 8.71e-05%, nfe); Associated with neuropathy, hereditary sensory and autonomic, type 1C.

What condition is associated with SPTLC2 p.Pro5Ser (c.13C>T)?

SPTLC2 p.Pro5Ser (c.13C>T) is associated with neuropathy, hereditary sensory and autonomic, type 1C (ClinVar).

How common is SPTLC2 p.Pro5Ser (c.13C>T) in the general population?

SPTLC2 p.Pro5Ser (c.13C>T) is very rare (popmax 8.71e-05%, nfe) (gnomAD).

What do computational predictors say about SPTLC2 p.Pro5Ser (c.13C>T)?

AlphaMissense predicts likely benign (score 0.0746) — an in-silico prediction, not a clinical call.

SPTLC2 p.Pro5Ser

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.13C>T · rs1473189491 · VCV968734

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0746 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.71e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuropathy, hereditary sensory and autonomic, type 1C

Computational evidence

Protein change
AlphaMissense	0.0746	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 0.47, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 104 kb · p 3.9e-14 · regional, not allelic
Overall
CADD	19.62	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.71e-05% European (non-Finnish) · 1/1,147,858 alleles

Overall 6.5e-05% 1/1,537,738 alleles · very rare exomes 1/1,385,416 · genomes 0/152,322 · joint denominator

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.Pro5Ser
Coding: c.13C>T
MANE Select: NM_004863
dbSNP: rs1473189491
Type: single nucleotide variant
Location: chr14:77616567 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.47 · 17 PDB

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.Pro5Leu Uncertain significance ★ ⚠ same residue
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

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-pro5ser (accessed [today's date]).

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