Is TECPR2 p.Pro1344Ala (c.4030C>G) pathogenic?

TECPR2 p.Pro1344Ala (c.4030C>G) is classified Uncertain significance in TECPR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-31). AlphaMissense: likely benign (0.1199); Very rare (popmax 0.00168%, amr); Associated with hereditary spastic paraplegia 49.

What condition is associated with TECPR2 p.Pro1344Ala (c.4030C>G)?

TECPR2 p.Pro1344Ala (c.4030C>G) is associated with hereditary spastic paraplegia 49 (ClinVar).

How common is TECPR2 p.Pro1344Ala (c.4030C>G) in the general population?

TECPR2 p.Pro1344Ala (c.4030C>G) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about TECPR2 p.Pro1344Ala (c.4030C>G)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

TECPR2 p.Pro1344Ala

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.4030C>G · rs763133422 · VCV540300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary spastic paraplegia 49

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 122 kb · p 2.1e-10 · regional, not allelic
Overall
CADD	22.4	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 0.00168% Admixed American · 1/59,612 alleles

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

Overall 0.000373% 6/1,609,024 alleles · very rare exomes 6/1,456,714 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,612
Remaining individualsnot grpmax-eligible	0.00161%	62,290
European (non-Finnish)	0.000339%	294,558

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.Pro1344Ala
Coding: c.4030C>G
MANE Select: NM_014844
dbSNP: rs763133422
Type: single nucleotide variant
Location: chr14:102497668 (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.Pro1344= Likely benign ★★ 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-pro1344ala (accessed [today's date]).

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