Is TECPR2 p.Ile683Val (c.2047A>G) pathogenic?

TECPR2 p.Ile683Val (c.2047A>G) is classified Benign/Likely benign in TECPR2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.077); Common (popmax 39.5%, mid) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 49.

What condition is associated with TECPR2 p.Ile683Val (c.2047A>G)?

TECPR2 p.Ile683Val (c.2047A>G) is associated with hereditary spastic paraplegia 49 (ClinVar).

What do computational predictors say about TECPR2 p.Ile683Val (c.2047A>G)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

TECPR2 p.Ile683Val

Q: How common is TECPR2 p.Ile683Val (c.2047A>G) in the general population?

TECPR2 p.Ile683Val (c.2047A>G) is common (popmax 39.5%, mid) — 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.2047A>G · rs10149146 · VCV380891

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 39.5%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 49

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.002	strongly benign-leaning
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.2	GERP -3.2
Regional constraint	o/e 0.85	unconstrained · MANE · 122 kb · p 2.1e-10 · regional, not allelic
Overall
CADD	0.009	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 39.5% Middle Eastern · 2,393/6,062 alleles

Filtering AF 38.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 37.6%

Overall 31.1% 502,511/1,613,380 alleles · common exomes 462,967/1,461,166 · genomes 39,544/152,214 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	40.2%	2
Middle Easterngrpmax	39.5%	3
European (non-Finnish)	33.2%	3
South Asian	32.7%	3
Remaining individualsnot grpmax-eligible	31.2%	3
Admixed American	25.5%	4
Finnishnot grpmax-eligible	20.5%	5
Amishnot grpmax-eligible	20.2%	5
East Asian	17%	6
African / African-American	14.5%	7

Ashkenazi Jewish 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.Ile683Val
Coding: c.2047A>G
MANE Select: NM_014844
dbSNP: rs10149146
Type: single nucleotide variant
Location: chr14:102434864 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.27
Residue 683: a UniProt-annotated variant site (in)

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-ile683val (accessed [today's date]).

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