Is TECPR2 p.Val516Met (c.1546G>A) pathogenic?

TECPR2 p.Val516Met (c.1546G>A) is classified Conflicting classifications of pathogenicity in TECPR2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.0708); Ultra-rare (popmax 0.0595%, afr); Associated with Inborn genetic diseases.

What condition is associated with TECPR2 p.Val516Met (c.1546G>A)?

TECPR2 p.Val516Met (c.1546G>A) is associated with Inborn genetic diseases, hereditary spastic paraplegia 49 (ClinVar).

How common is TECPR2 p.Val516Met (c.1546G>A) in the general population?

TECPR2 p.Val516Met (c.1546G>A) is ultra-rare (popmax 0.0595%, afr) (gnomAD).

What do computational predictors say about TECPR2 p.Val516Met (c.1546G>A)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

TECPR2 p.Val516Met

c.1546G>A · rs141697267 · VCV970207

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0595%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.008	strongly benign-leaning
SaProt	LLR -7.08	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 -0.38	GERP -3.5
Regional constraint	o/e 0.85	unconstrained · MANE · 122 kb · p 2.1e-10 · regional, not allelic
Overall
CADD	6.645	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 0.0595% African / African-American · 43/72,248 alleles

Filtering AF 0.0454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0404%

Overall 0.0151% 230/1,520,148 alleles · ultra-rare exomes 183/1,367,846 · genomes 47/152,302 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0595%	1,680
European (non-Finnish)	0.0154%	6,481
Remaining individualsnot grpmax-eligible	0.0137%	7,304
Admixed American	0.00431%	23,175
East Asian	0.00227%	44,040
South Asian	0.00135%	74,010

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.Val516Met
Coding: c.1546G>A
MANE Select: NM_014844
dbSNP: rs141697267
Type: single nucleotide variant
Location: chr14:102434363 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.27
Residue 516: the 'disordered' region

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 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-val516met (accessed [today's date]).

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