Is TECPR2 p.Val320Ile (c.958G>A) pathogenic?

TECPR2 p.Val320Ile (c.958G>A) is classified Benign in TECPR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0583); Common (popmax 98.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 49.

What condition is associated with TECPR2 p.Val320Ile (c.958G>A)?

TECPR2 p.Val320Ile (c.958G>A) is associated with hereditary spastic paraplegia 49 (ClinVar).

What do computational predictors say about TECPR2 p.Val320Ile (c.958G>A)?

AlphaMissense predicts likely benign (score 0.0583) — an in-silico prediction, not a clinical call.

TECPR2 p.Val320Ile

Q: How common is TECPR2 p.Val320Ile (c.958G>A) in the general population?

TECPR2 p.Val320Ile (c.958G>A) is common (popmax 98.8%, 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.958G>A · rs1309353 · VCV380873

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0583 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 98.8%, afr) — 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	0.0583	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -6.22	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 0.35	GERP -3.5
Regional constraint	o/e 0.85	unconstrained · MANE · 122 kb · p 2.1e-10 · regional, not allelic
Overall
CADD	7.295	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 98.8% African / African-American · 62,156/62,940 alleles

Filtering AF 98.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 97.8%

Overall 93.6% 1,399,554/1,495,682 alleles · common exomes 1,277,300/1,364,538 · genomes 122,254/131,144 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	98.8%	1
Middle Eastern	97.8%	1
Ashkenazi Jewishnot grpmax-eligible	96.5%	1
European (non-Finnish)	95.2%	1
South Asian	93.6%	1
Remaining individualsnot grpmax-eligible	92.9%	1
Finnishnot grpmax-eligible	89.9%	1
Amishnot grpmax-eligible	88.2%	1
Admixed American	70.1%	1
East Asian	65.5%	2

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.Val320Ile
Coding: c.958G>A
MANE Select: NM_014844
dbSNP: rs1309353
Type: single nucleotide variant
Location: chr14:102428256 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.27
Residue 320: 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 p.Val320= 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-val320ile (accessed [today's date]).

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