Is SPTLC1 p.Ser331= (c.993C>T) pathogenic?

SPTLC1 p.Ser331= (c.993C>T) is classified Likely benign in SPTLC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0164%, mid); Associated with Charcot-Marie-Tooth disease.

What condition is associated with SPTLC1 p.Ser331= (c.993C>T)?

SPTLC1 p.Ser331= (c.993C>T) is associated with Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy type 1 (ClinVar).

How common is SPTLC1 p.Ser331= (c.993C>T) in the general population?

SPTLC1 p.Ser331= (c.993C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

SPTLC1 p.Ser331=

c.993C>T · rs141150508 · VCV917299

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Charcot-Marie-Tooth disease

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 -5.3	GERP -3.7
Overall
CADD	0.889	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00223% 36/1,613,834 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
South Asian	0.011%	9,109
East Asian	0.00891%	11,223
Remaining individualsnot grpmax-eligible	0.0048%	20,826
European (non-Finnish)	0.00144%	69,405
African / African-American	0.00134%	74,900

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: SPTLC1
Protein: p.Ser331=
Coding: c.993C>T
MANE Select: NM_006415
dbSNP: rs141150508
Type: single nucleotide variant
Location: chr9:92047260 (GRCh38)
Gene constraint: LOEUF 1.068 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.04 · 17 PDB
Residue 331: a UniProt-annotated variant site (in hsan1a; severe form with early onset; reduced canonical activity towards serine and increased production of deoxysphingolipids; no effect on subcellular location at the endoplasmic reticulum); a UniProt-annotated variant site (in als27 and hsan1a; reduced canonical activity towards serine and increased production of deoxysphingolipids); an α-helix

Full SPTLC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary sensory and autonomic neuropathy type 1

Similar variants

SPTLC1 p.Ser331Tyr Pathogenic ★★ same residue
SPTLC1 p.Ser331Phe Pathogenic ★ same residue
SPTLC1 p.Cys133Trp Pathogenic ★★ same condition
SPTLC1 p.Cys133Tyr Pathogenic ★★ same condition
SPTLC1 p.Val144Asp Pathogenic/Likely pathogenic ★★ same condition
SPTLC1 c.1137-1G>A Uncertain significance ★★ same condition
SPTLC1 c.1255-3C>T Uncertain significance ★★ same condition
SPTLC1 c.1329-1G>T 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/sptlc1-p-ser331 (accessed [today's date]).

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