Is TG p.Arg1691Cys (c.5071C>T) pathogenic?

TG p.Arg1691Cys (c.5071C>T) is classified Conflicting classifications of pathogenicity in TG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2253); Rare (popmax 0.671%, sas); Associated with thyroid dyshormonogenesis 3.

What condition is associated with TG p.Arg1691Cys (c.5071C>T)?

TG p.Arg1691Cys (c.5071C>T) is associated with thyroid dyshormonogenesis 3 (ClinVar).

How common is TG p.Arg1691Cys (c.5071C>T) in the general population?

TG p.Arg1691Cys (c.5071C>T) is rare (popmax 0.671%, 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.Arg1691Cys (c.5071C>T)?

AlphaMissense predicts likely benign (score 0.2253) — an in-silico prediction, not a clinical call.

TG p.Arg1691Cys

c.5071C>T · rs375968742 · VCV725439

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2253 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.671%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

thyroid dyshormonogenesis 3

Computational evidence

Protein change
AlphaMissense	0.2253	likely benign
REVEL	0.087	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 0.8	GERP -3.9
Regional constraint	o/e 1.04	unconstrained · MANE · 268 kb · p 0.022 · regional, not allelic
Overall
CADD	15.63	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 0.671% South Asian · 611/91,084 alleles

Filtering AF 0.627% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.609%

Overall 0.0431% 696/1,614,212 alleles · rare exomes 639/1,461,892 · genomes 57/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.671%	149
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0288%	3,473
African / African-American	0.0213%	4,690
East Asian	0.00891%	11,222
Admixed American	0.005%	20,009
European (non-Finnish)	0.0033%	30,258

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.Arg1691Cys
Coding: c.5071C>T
MANE Select: NM_003235
dbSNP: rs375968742
Type: single nucleotide variant
Location: chr8:132941380 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Residue 1691: 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 p.Arg1691Leu Uncertain significance ★ ⚠ 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-arg1691cys (accessed [today's date]).

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