Is TECPR2 p.Arg1336Trp (c.4006C>T) pathogenic?

TECPR2 p.Arg1336Trp (c.4006C>T) is classified Uncertain significance in TECPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-01). AlphaMissense: likely pathogenic (0.9679); Very rare (popmax 0.00224%, eas); Associated with hereditary spastic paraplegia 49.

What condition is associated with TECPR2 p.Arg1336Trp (c.4006C>T)?

TECPR2 p.Arg1336Trp (c.4006C>T) is associated with hereditary spastic paraplegia 49 (ClinVar).

How common is TECPR2 p.Arg1336Trp (c.4006C>T) in the general population?

TECPR2 p.Arg1336Trp (c.4006C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about TECPR2 p.Arg1336Trp (c.4006C>T)?

AlphaMissense predicts likely pathogenic (score 0.9679) — an in-silico prediction, not a clinical call.

TECPR2 p.Arg1336Trp

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.4006C>T · rs778817517 · VCV996005

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary spastic paraplegia 49

Computational evidence

Protein change
AlphaMissense	0.9679	likely pathogenic · top 5% in TECPR2
REVEL	0.608	indeterminate
SaProt	LLR -15.72	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 0.66, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 122 kb · p 2.1e-10 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00224% East Asian · 1/44,698 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000901%

Overall 0.00193% 31/1,609,434 alleles · very rare exomes 31/1,457,100 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,901
Finnishnot grpmax-eligible	0.0032%	31,265
East Asiangrpmax	0.00224%	44,698
European (non-Finnish)	0.0017%	58,926
African / African-American	0.00133%	74,976

Remaining individuals 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.Arg1336Trp
Coding: c.4006C>T
MANE Select: NM_014844
dbSNP: rs778817517
Type: single nucleotide variant
Location: chr14:102497644 (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 p.Arg1336Gln Uncertain significance ★★ ⚠ same residue
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

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-arg1336trp (accessed [today's date]).

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