Is SPTLC2 p.Pro137= (c.411A>C) pathogenic?

SPTLC2 p.Pro137= (c.411A>C) is classified Likely benign in SPTLC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-28). Very rare (popmax 0.000508%, nfe); Associated with neuropathy, hereditary sensory and autonomic, type 1C.

What condition is associated with SPTLC2 p.Pro137= (c.411A>C)?

SPTLC2 p.Pro137= (c.411A>C) is associated with neuropathy, hereditary sensory and autonomic, type 1C (ClinVar).

How common is SPTLC2 p.Pro137= (c.411A>C) in the general population?

SPTLC2 p.Pro137= (c.411A>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

SPTLC2 p.Pro137=

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.411A>C · VCV3704418

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

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.
REVEL	0.22	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.7	GERP -3.7
Overall
CADD	0.558	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,020 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000743% 12/1,614,008 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00781%	12,807
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)grpmax	0.000508%	196,670

Finnish 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: SPTLC2
Protein: p.Pro137=
Coding: c.411A>C
MANE Select: NM_004863
Type: single nucleotide variant
Location: chr14:77579026 (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.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-pro137 (accessed [today's date]).

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