Is TELO2 p.Pro497Ser (c.1489C>T) pathogenic?

TELO2 p.Pro497Ser (c.1489C>T) is classified Uncertain significance in TELO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-21). AlphaMissense: ambiguous (0.4963); Ultra-rare (popmax 0.062%, nfe).

How common is TELO2 p.Pro497Ser (c.1489C>T) in the general population?

TELO2 p.Pro497Ser (c.1489C>T) is ultra-rare (popmax 0.062%, nfe) (gnomAD).

What do computational predictors say about TELO2 p.Pro497Ser (c.1489C>T)?

AlphaMissense predicts ambiguous (score 0.4963) — an in-silico prediction, not a clinical call.

TELO2 p.Pro497Ser

c.1489C>T · rs140861723 · VCV1471246

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4963 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.062%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4963	ambiguous
REVEL	0.228	benign-leaning
SaProt	LLR -10.33	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 16 kb · p 0.22 · regional, not allelic
Overall
CADD	24.8	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 0.062% European (non-Finnish) · 731/1,179,976 alleles

Filtering AF 0.0582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0567%

Overall 0.0488% 787/1,613,344 alleles · ultra-rare exomes 743/1,460,964 · genomes 44/152,380 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.062%	1,614
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.048%	2,083
African / African-American	0.0133%	7,508
Admixed American	0.01%	10,005
South Asian	0.00549%	18,218
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
East Asian	0.00223%	44,888

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.Pro497Ser
Coding: c.1489C>T
MANE Select: NM_016111
dbSNP: rs140861723
Type: single nucleotide variant
Location: chr16:1502063 (GRCh38)
Gene constraint: LOEUF 1.03 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.74 · 4 PDB

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

Similar variants

TELO2 p.Pro497His Uncertain significance ★ ⚠ same residue
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

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-pro497ser (accessed [today's date]).

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