Is TG p.Pro2202Arg (c.6605C>G) pathogenic?

TG p.Pro2202Arg (c.6605C>G) is classified Uncertain significance in TG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-05). AlphaMissense: likely benign (0.0928); Rare (popmax 0.154%, sas); Associated with thyroid dyshormonogenesis 3.

What condition is associated with TG p.Pro2202Arg (c.6605C>G)?

TG p.Pro2202Arg (c.6605C>G) is associated with thyroid dyshormonogenesis 3 (ClinVar).

How common is TG p.Pro2202Arg (c.6605C>G) in the general population?

TG p.Pro2202Arg (c.6605C>G) is rare (popmax 0.154%, sas) (gnomAD).

How is Familial thyroid dyshormonogenesis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TG p.Pro2202Arg (c.6605C>G)?

AlphaMissense predicts likely benign (score 0.0928) — an in-silico prediction, not a clinical call.

TG p.Pro2202Arg

c.6605C>G · rs150133670 · VCV910240

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0928 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.154%, sas)

Conditions

thyroid dyshormonogenesis 3

Computational evidence

Protein change
AlphaMissense	0.0928	likely benign
REVEL	0.303	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.04	GERP -0.77
Regional constraint	o/e 1.04	unconstrained · MANE · 268 kb · p 0.022 · regional, not allelic
Overall
CADD	4.06	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.154% South Asian · 140/91,086 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.125%

Overall 0.045% 726/1,614,206 alleles · rare exomes 671/1,461,890 · genomes 55/152,316 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.154%	651
Middle Eastern	0.099%	1,010
Admixed American	0.08%	1,251
European (non-Finnish)	0.0423%	2,365
Remaining individualsnot grpmax-eligible	0.0384%	2,605
African / African-American	0.00666%	15,010
Finnishnot grpmax-eligible	0.00468%	21,345
East Asian	0.00223%	44,878

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.Pro2202Arg
Coding: c.6605C>G
MANE Select: NM_003235
dbSNP: rs150133670
Type: single nucleotide variant
Location: chr8:133017820 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Residue 2202: the 'cholinesterase-like (chel)' region; a β-strand

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

Disease context

thyroid dyshormonogenesis 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thyroid dyshormonogenesis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

TG c.274+2T>G Pathogenic ★★ same condition
TG c.3634+1G>A Likely pathogenic ★★ same condition
TG c.5686+1G>A Pathogenic ★★ same condition
TG c.5686+1G>T Pathogenic ★★ same condition
TG c.638+5G>A Pathogenic/Likely pathogenic ★★ same condition
TG c.6782+1G>T Likely pathogenic ★★ same condition
TG c.7863-1G>A Likely pathogenic ★★ same condition
TG p.Arg1530Ter Pathogenic ★★ 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-pro2202arg (accessed [today's date]).

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