Is TECPR2 p.Pro538= (c.1614A>G) pathogenic?

TECPR2 p.Pro538= (c.1614A>G) is classified Benign in TECPR2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 5.61%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 49.

What condition is associated with TECPR2 p.Pro538= (c.1614A>G)?

TECPR2 p.Pro538= (c.1614A>G) is associated with hereditary spastic paraplegia 49, hereditary spastic paraplegia (ClinVar).

TECPR2 p.Pro538=

Q: How common is TECPR2 p.Pro538= (c.1614A>G) in the general population?

TECPR2 p.Pro538= (c.1614A>G) is common (popmax 5.61%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1614A>G · rs17791240 · VCV380928

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 5.61%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary spastic paraplegia 49

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 -0.098	GERP -3.5
Overall
CADD	0.848	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.61% African / African-American · 4,049/72,238 alleles

Filtering AF 5.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4%

Overall 3.41% 52,168/1,531,524 alleles · common exomes 45,805/1,379,236 · genomes 6,363/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.61%	18
Middle Eastern	5.37%	19
Admixed American	5.26%	19
Amishnot grpmax-eligible	4.93%	20
Ashkenazi Jewishnot grpmax-eligible	4.65%	22
East Asian	3.96%	25
Finnishnot grpmax-eligible	3.92%	26
South Asian	3.86%	26
Remaining individualsnot grpmax-eligible	3.6%	28
European (non-Finnish)	3.07%	33

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.Pro538=
Coding: c.1614A>G
MANE Select: NM_014844
dbSNP: rs17791240
Type: single nucleotide variant
Location: chr14:102434431 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.27
Residue 538: the 'disordered' region

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

Also linked: hereditary spastic paraplegia

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

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

TECPR2 c.1084+2T>C Likely pathogenic ★★ same condition
TECPR2 c.1418-2A>G Likely pathogenic ★★ same condition
TECPR2 c.2753-1G>A Likely pathogenic ★★ same condition
TECPR2 p.Gln1189Ter Pathogenic/Likely pathogenic ★★ same condition
TECPR2 p.Gln191Ter Pathogenic/Likely pathogenic ★★ same condition
TECPR2 p.Gln852Ter Pathogenic ★★ same condition
TECPR2 p.Trp1024Ter Pathogenic ★★ same condition
TECPR2 p.Trp1288Ter 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-pro538 (accessed [today's date]).

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