Is TG p.Arg988Pro (c.2963G>C) pathogenic?

TG p.Arg988Pro (c.2963G>C) is classified Benign/Likely benign in TG (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-11). AlphaMissense: likely benign (0.195); Common (popmax 9.17%, afr) — too common for a highly-penetrant pathogenic allele; Associated with thyroid dyshormonogenesis 3.

What condition is associated with TG p.Arg988Pro (c.2963G>C)?

TG p.Arg988Pro (c.2963G>C) is associated with thyroid dyshormonogenesis 3 (ClinVar).

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.Arg988Pro (c.2963G>C)?

AlphaMissense predicts likely benign (score 0.195) — an in-silico prediction, not a clinical call.

TG p.Arg988Pro

Q: How common is TG p.Arg988Pro (c.2963G>C) in the general population?

TG p.Arg988Pro (c.2963G>C) is common (popmax 9.17%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2963G>C · rs16893332 · VCV361933

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.195 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.17%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

thyroid dyshormonogenesis 3

Computational evidence

Protein change
AlphaMissense	0.195	likely benign
REVEL	0.089	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 0.32	GERP -2.7, phastCons 0.004
Regional constraint	o/e 1.04	unconstrained · MANE · 268 kb · p 0.022 · regional, not allelic
Overall
CADD	13.27	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 9.17% African / African-American · 6,877/74,976 alleles

Filtering AF 8.99% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.92%

Overall 1.11% 17,872/1,614,008 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.17%	11
East Asian	8.83%	11
Finnishnot grpmax-eligible	5.32%	19
Remaining individualsnot grpmax-eligible	1.72%	58
Ashkenazi Jewishnot grpmax-eligible	0.976%	102
South Asian	0.858%	116
Admixed American	0.68%	147
Middle Eastern	0.495%	202
European (non-Finnish)	0.0886%	1,129

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.Arg988Pro
Coding: c.2963G>C
MANE Select: NM_003235
dbSNP: rs16893332
Type: single nucleotide variant
Location: chr8:132893891 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Residue 988: a disulfide bond; a UniProt-annotated variant site (in); the thyroglobulin type-1 8 domain

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.Arg988His Conflicting classifications of pathogenicity ★ ⚠ same residue
TG p.Arg988= Likely benign ★ same residue
TG p.Arg988Ser 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

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-arg988pro (accessed [today's date]).

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