Is TG p.Pro1559Ser (c.4675C>T) pathogenic?

TG p.Pro1559Ser (c.4675C>T) is classified Uncertain significance in TG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.076); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TG p.Pro1559Ser (c.4675C>T)?

TG p.Pro1559Ser (c.4675C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TG p.Pro1559Ser (c.4675C>T) in the general population?

TG p.Pro1559Ser (c.4675C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TG p.Pro1559Ser (c.4675C>T)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

TG p.Pro1559Ser

c.4675C>T · rs2490364590 · VCV2264574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -0.57
Regional constraint	o/e 1.04	unconstrained · MANE · 268 kb · p 0.022 · regional, not allelic
Overall
CADD	1.039	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,968 alleles

Overall 6.84e-05% 1/1,461,808 alleles · very rare

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: TG
Protein: p.Pro1559Ser
Coding: c.4675C>T
MANE Select: NM_003235
dbSNP: rs2490364590
Type: single nucleotide variant
Location: chr8:132923484 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Residue 1559: a disulfide bond; the thyroglobulin type-1 11 domain

Full TG 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

Similar variants

TG p.Pro1559= Likely benign ★ same residue
TG p.Ala1033Val Uncertain significance ★★ ⚠ same condition
TG p.Ala1419Glu Uncertain significance ★★ same condition
TG p.Ala1419Val Uncertain significance ★★ ⚠ same condition
TG p.Ala1583Val Uncertain significance ★★ ⚠ same condition
TG p.Ala1631Ser Uncertain significance ★★ ⚠ same condition
TG p.Ala402Gly Uncertain significance ★★ ⚠ same condition
TG p.Ala457Val Uncertain significance ★★ 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/tg-p-pro1559ser (accessed [today's date]).

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