Is TG p.Pro2315= (c.6945G>A) pathogenic?

TG p.Pro2315= (c.6945G>A) is classified Conflicting classifications of pathogenicity in TG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-23). Very rare (popmax 0.0022%, sas); Associated with thyroid dyshormonogenesis 3.

What condition is associated with TG p.Pro2315= (c.6945G>A)?

TG p.Pro2315= (c.6945G>A) is associated with thyroid dyshormonogenesis 3 (ClinVar).

How common is TG p.Pro2315= (c.6945G>A) in the general population?

TG p.Pro2315= (c.6945G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Familial thyroid dyshormonogenesis inherited?

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

TG p.Pro2315=

c.6945G>A · rs769872031 · VCV361988

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

thyroid dyshormonogenesis 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.049	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.2	GERP -5.2
Overall
CADD	4.704	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00142% 23/1,614,072 alleles · very rare exomes 19/1,461,886 · genomes 4/152,186 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
European (non-Finnish)	0.00161%	62,107
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,928

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.Pro2315=
Coding: c.6945G>A
MANE Select: NM_003235
dbSNP: rs769872031
Type: single nucleotide variant
Location: chr8:133022059 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Residue 2315: the 'cholinesterase-like (chel)' region

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 p.Pro2315Leu Likely benign ★ same residue
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

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-pro2315 (accessed [today's date]).

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