Is TSR2 p.Pro166Ser (c.496C>T) pathogenic?

TSR2 p.Pro166Ser (c.496C>T) is classified Uncertain significance in TSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.0656); Absent from gnomAD v4.1.

How common is TSR2 p.Pro166Ser (c.496C>T) in the general population?

TSR2 p.Pro166Ser (c.496C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSR2 p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

TSR2 p.Pro166Ser

c.496C>T · VCV4730952

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.15	GERP -3, phastCons 0.01
Regional constraint	o/e 0.90	unconstrained · MANE · 466 bp · p 0.42 · regional, not allelic
Overall
CADD	8.607	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSR2
Protein: p.Pro166Ser
Coding: c.496C>T
MANE Select: NM_058163
Type: single nucleotide variant
Location: chrX:54444470 (GRCh38)
Structure: AlphaFold pLDDT 74.60
Residue 166: the 'disordered' region

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

Similar variants

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
FGD1 p.Phe873= Benign/Likely benign ★★ same type
TSR2 c.82-58C>T Benign ★★ 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-pro166ser (accessed [today's date]).

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