Is TSR2 p.Pro169= (c.507A>G) pathogenic?

TSR2 p.Pro169= (c.507A>G) is classified Uncertain significance in TSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-23). Very rare (popmax 0.00438%, amr).

How common is TSR2 p.Pro169= (c.507A>G) in the general population?

TSR2 p.Pro169= (c.507A>G) is very rare (popmax 0.00438%, amr) (gnomAD).

TSR2 p.Pro169=

c.507A>G · rs1370514349 · VCV2876309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00438%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.68, phastCons 1
Overall
CADD	8.586	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00438% Admixed American · 2/45,692 alleles

Filtering AF 0.000726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000271%

Overall 0.000248% 3/1,208,209 alleles · very rare exomes 2/1,096,332 · genomes 1/111,877 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00438%	22,846
European (non-Finnish)	0.000112%	893,847

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: TSR2
Protein: p.Pro169=
Coding: c.507A>G
MANE Select: NM_058163
dbSNP: rs1370514349
Type: single nucleotide variant
Location: chrX:54444481 (GRCh38)
Structure: AlphaFold pLDDT 74.60
Residue 169: the 'disordered' region

Full TSR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TSR2 p.Pro169Ala Uncertain significance ★ ⚠ same residue
TSR2 p.Pro169Ser Uncertain significance ★ ⚠ same residue
TSR2 p.Ala8Pro Uncertain significance ★★ ⚠ same type
TSR2 p.Arg56Cys Uncertain significance ★★ ⚠ same type
TSR2 p.Asn75Asp Uncertain significance ★★ ⚠ same type
TSR2 p.Glu6Gly Uncertain significance ★★ ⚠ same type
TSR2 p.Gly35Ala Uncertain significance ★★ ⚠ same type
TSR2 p.His98Tyr 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/tsr2-p-pro169 (accessed [today's date]).

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