Is TECPR2 p.Ser415Tyr (c.1244C>A) pathogenic?

TECPR2 p.Ser415Tyr (c.1244C>A) is classified Uncertain significance in TECPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-19). AlphaMissense: ambiguous (0.4887); Very rare (popmax 0.00446%, eas); Associated with hereditary spastic paraplegia.

What condition is associated with TECPR2 p.Ser415Tyr (c.1244C>A)?

TECPR2 p.Ser415Tyr (c.1244C>A) is associated with hereditary spastic paraplegia, hereditary spastic paraplegia 49 (ClinVar).

How common is TECPR2 p.Ser415Tyr (c.1244C>A) in the general population?

TECPR2 p.Ser415Tyr (c.1244C>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about TECPR2 p.Ser415Tyr (c.1244C>A)?

AlphaMissense predicts ambiguous (score 0.4887) — an in-silico prediction, not a clinical call.

TECPR2 p.Ser415Tyr

c.1244C>A · rs1239046327 · VCV1344145

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.4887	ambiguous
REVEL	0.242	benign-leaning
SaProt	LLR -11.64	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,612,926 alleles · very rare exomes 4/1,460,706 · genomes 2/152,220 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,444
European (non-Finnish)	0.000339%	294,934

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.Ser415Tyr
Coding: c.1244C>A
MANE Select: NM_014844
dbSNP: rs1239046327
Type: single nucleotide variant
Location: chr14:102431955 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.27
Residue 415: the 'disordered' region

Full TECPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 49

Similar variants

TECPR2 p.Ser415= Likely benign ★ same residue
TECPR2 p.Ser415Ala 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-ser415tyr (accessed [today's date]).

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