Is TELO2 p.Ala453Val (c.1358C>T) pathogenic?

TELO2 p.Ala453Val (c.1358C>T) is classified Uncertain significance in TELO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-19). AlphaMissense: likely benign (0.0759); Ultra-rare (popmax 0.0101%, amr).

How common is TELO2 p.Ala453Val (c.1358C>T) in the general population?

TELO2 p.Ala453Val (c.1358C>T) is ultra-rare (popmax 0.0101%, amr) (gnomAD).

What do computational predictors say about TELO2 p.Ala453Val (c.1358C>T)?

AlphaMissense predicts likely benign (score 0.0759) — an in-silico prediction, not a clinical call.

TELO2 p.Ala453Val

c.1358C>T · rs774629694 · VCV2146903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0759 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0759	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.77	donor gain · deltas
Pangolin	Δ0.51	gain · loss 0.24 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.09	GERP -3.9
Regional constraint	o/e 1.04	unconstrained · MANE · 16 kb · p 0.22 · regional, not allelic
Overall
CADD	21.7	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 0.0101% Admixed American · 6/59,494 alleles

Filtering AF 0.00431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00297%

Overall 0.000809% 13/1,607,686 alleles · ultra-rare exomes 11/1,455,508 · genomes 2/152,178 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0101%	9,916
East Asian	0.00223%	44,748
Remaining individualsnot grpmax-eligible	0.00161%	62,140
European (non-Finnish)	0.000425%	235,423

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: TELO2
Protein: p.Ala453Val
Coding: c.1358C>T
MANE Select: NM_016111
dbSNP: rs774629694
Type: single nucleotide variant
Location: chr16:1501496 (GRCh38)
Gene constraint: LOEUF 1.03 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.74 · 4 PDB
Residue 453: the 'disordered' region

Full TELO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TELO2 c.2034+2T>C Likely pathogenic ★★ same type
TELO2 c.2291+1G>C Likely pathogenic ★★ same type
TELO2 p.Arg403Ter Pathogenic/Likely pathogenic ★★ same type
TELO2 p.Arg609His Pathogenic/Likely pathogenic ★★ same type
TELO2 p.Cys367Phe Pathogenic/Likely pathogenic ★★ same type
TELO2 c.830+5G>T Uncertain significance ★★ same type
TELO2 p.Ala198Val Uncertain significance ★★ ⚠ same type
TELO2 p.Ala323Pro Uncertain significance ★★ ⚠ same type

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/telo2-p-ala453val (accessed [today's date]).

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