Is TECPR2 p.Glu405Lys (c.1213G>A) pathogenic?

TECPR2 p.Glu405Lys (c.1213G>A) is classified Uncertain significance in TECPR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-02). AlphaMissense: likely benign (0.2219); Ultra-rare (popmax 0.029%, eas); Associated with hereditary spastic paraplegia 49.

What condition is associated with TECPR2 p.Glu405Lys (c.1213G>A)?

TECPR2 p.Glu405Lys (c.1213G>A) is associated with hereditary spastic paraplegia 49 (ClinVar).

How common is TECPR2 p.Glu405Lys (c.1213G>A) in the general population?

TECPR2 p.Glu405Lys (c.1213G>A) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about TECPR2 p.Glu405Lys (c.1213G>A)?

AlphaMissense predicts likely benign (score 0.2219) — an in-silico prediction, not a clinical call.

TECPR2 p.Glu405Lys

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.1213G>A · rs148556964 · VCV582659

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2219 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 49

Computational evidence

Protein change
AlphaMissense	0.2219	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -7.85	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 6.6	GERP 0.55, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 122 kb · p 2.1e-10 · regional, not allelic
Overall
CADD	24.5	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 0.029% East Asian · 13/44,798 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00211% 34/1,610,894 alleles · ultra-rare exomes 33/1,458,744 · genomes 1/152,150 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,446
African / African-American	0.00401%	24,959
Admixed American	0.00167%	59,964
Finnishnot grpmax-eligible	0.00158%	63,484
European (non-Finnish)	0.00136%	73,617

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.Glu405Lys
Coding: c.1213G>A
MANE Select: NM_014844
dbSNP: rs148556964
Type: single nucleotide variant
Location: chr14:102431924 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.27
Residue 405: 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

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-glu405lys (accessed [today's date]).

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