Is TECPR2 p.Thr208Ala (c.622A>G) pathogenic?

TECPR2 p.Thr208Ala (c.622A>G) is classified Uncertain significance in TECPR2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-08-06). AlphaMissense: likely benign (0.0725); Ultra-rare (popmax 0.0164%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TECPR2 p.Thr208Ala (c.622A>G)?

TECPR2 p.Thr208Ala (c.622A>G) is associated with Inborn genetic diseases, hereditary spastic paraplegia 49 (ClinVar).

How common is TECPR2 p.Thr208Ala (c.622A>G) in the general population?

TECPR2 p.Thr208Ala (c.622A>G) is ultra-rare (popmax 0.0164%, nfe) (gnomAD).

What do computational predictors say about TECPR2 p.Thr208Ala (c.622A>G)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

TECPR2 p.Thr208Ala

c.622A>G · rs536338550 · VCV649453

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -6.52	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 0.76	GERP -0.79, phastCons 0.02
Regional constraint	o/e 0.85	unconstrained · MANE · 122 kb · p 2.1e-10 · regional, not allelic
Overall
CADD	14.04	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 0.0164% European (non-Finnish) · 194/1,180,028 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0126% 203/1,614,090 alleles · ultra-rare exomes 183/1,461,838 · genomes 20/152,252 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0164%	6,083
Admixed American	0.00833%	11,999
Remaining individualsnot grpmax-eligible	0.0064%	15,621

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.Thr208Ala
Coding: c.622A>G
MANE Select: NM_014844
dbSNP: rs536338550
Type: single nucleotide variant
Location: chr14:102414777 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 49

Similar variants

TECPR2 p.Thr208Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
TECPR2 p.Thr208Arg 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

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-thr208ala (accessed [today's date]).

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