Is TECPR2 p.Leu440fs (c.1318_1319del) pathogenic?

TECPR2 p.Leu440fs (c.13181319del) is classified Pathogenic/Likely pathogenic in TECPR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-19). Very rare (popmax 0.00133%, afr); Associated with hereditary spastic paraplegia 49.

What condition is associated with TECPR2 p.Leu440fs (c.1318_1319del)?

TECPR2 p.Leu440fs (c.1318_1319del) is associated with hereditary spastic paraplegia 49 (ClinVar).

How common is TECPR2 p.Leu440fs (c.1318_1319del) in the general population?

TECPR2 p.Leu440fs (c.1318_1319del) is very rare (popmax 0.00133%, afr) (gnomAD).

TECPR2 p.Leu440fs

Q: How is Hereditary sensory and autonomic neuropathy due to TECPR2 mutation inherited?

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

c.1318_1319del · rs765874018 · VCV1065201

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary spastic paraplegia 49

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.1	GERP -0.27

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,054 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000744% 12/1,612,938 alleles · very rare exomes 12/1,460,616 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0111%	8,993
African / African-Americangrpmax	0.00133%	75,054
European (non-Finnish)	0.000339%	294,990

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: TECPR2
Protein: p.Leu440fs
Coding: c.1318_1319del
MANE Select: NM_014844
dbSNP: rs765874018
Type: Deletion
Location: chr14:102432029 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.27

Full TECPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 49 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary sensory and autonomic neuropathy due to TECPR2 mutation (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

TECPR2 c.222delG Pathogenic/Likely pathogenic ★★ same condition
TECPR2 p.Asn1277fs Pathogenic/Likely pathogenic ★★ same condition
TECPR2 p.Asn944fs Pathogenic/Likely pathogenic ★★ same condition
TECPR2 p.Asp259fs Pathogenic/Likely pathogenic ★★ same condition
TECPR2 p.Gln1263fs Pathogenic/Likely pathogenic ★★ same condition
TECPR2 p.Gly584fs Pathogenic/Likely pathogenic ★★ same condition
TECPR2 p.Leu1139fs Pathogenic ★★ same condition
TECPR2 p.Lys343fs Pathogenic/Likely pathogenic ★★ 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/tecpr2-p-leu440fs (accessed [today's date]).

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