Is TG p.Ser523Pro (c.1567T>C) pathogenic?

TG p.Ser523Pro (c.1567T>C) is classified Conflicting classifications of pathogenicity in TG (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0716); Rare (popmax 0.841%, mid); Associated with thyroid dyshormonogenesis 3.

What condition is associated with TG p.Ser523Pro (c.1567T>C)?

TG p.Ser523Pro (c.1567T>C) is associated with thyroid dyshormonogenesis 3 (ClinVar).

How common is TG p.Ser523Pro (c.1567T>C) in the general population?

TG p.Ser523Pro (c.1567T>C) is rare (popmax 0.841%, mid) (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.Ser523Pro (c.1567T>C)?

AlphaMissense predicts likely benign (score 0.0716) — an in-silico prediction, not a clinical call.

TG p.Ser523Pro

c.1567T>C · rs116062097 · VCV361915

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0716 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.841%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

thyroid dyshormonogenesis 3

Computational evidence

Protein change
AlphaMissense	0.0716	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.14	GERP -0.34
Regional constraint	o/e 1.04	unconstrained · MANE · 268 kb · p 0.022 · regional, not allelic
Overall
CADD	8.918	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 0.841% Middle Eastern · 51/6,062 alleles

Filtering AF 0.657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.592%

Overall 0.181% 2,926/1,614,156 alleles · rare exomes 2,720/1,461,880 · genomes 206/152,276 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.841%	119
Ashkenazi Jewishnot grpmax-eligible	0.307%	325
European (non-Finnish)	0.212%	472
Remaining individualsnot grpmax-eligible	0.206%	485
South Asian	0.0791%	1,265
Admixed American	0.075%	1,334
African / African-American	0.0426%	2,345
Finnishnot grpmax-eligible	0.00781%	12,804

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.Ser523Pro
Coding: c.1567T>C
MANE Select: NM_003235
dbSNP: rs116062097
Type: single nucleotide variant
Location: chr8:132886939 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Residue 523: the 'disordered' 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 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-ser523pro (accessed [today's date]).

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