Is TSHR p.Gln90Pro (c.269A>C) pathogenic?

TSHR p.Gln90Pro (c.269A>C) is classified Uncertain significance in TSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). AlphaMissense: ambiguous (0.4827); Ultra-rare (popmax 0.0165%, mid).

How common is TSHR p.Gln90Pro (c.269A>C) in the general population?

TSHR p.Gln90Pro (c.269A>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TSHR p.Gln90Pro (c.269A>C)?

AlphaMissense predicts ambiguous (score 0.4827) — an in-silico prediction, not a clinical call.

TSHR p.Gln90Pro

c.269A>C · VCV3336427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4827	ambiguous
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -13.17	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,058 alleles

Overall 0.000205% 3/1,461,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
African / African-American	0.00133%	74,984
European (non-Finnish)	8.48e-05%	1,179,440

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: TSHR
Protein: p.Gln90Pro
Coding: c.269A>C
MANE Select: NM_000369
Type: single nucleotide variant
Location: chr14:81068280 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 9 PDB

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

Similar variants

TSHR p.Gln90Ter Pathogenic ★ same residue
TSHR c.881+1G>A Pathogenic/Likely pathogenic ★★ same type
TSHR c.881+1G>T Pathogenic/Likely pathogenic ★★ same type
TSHR p.Ala553Thr Pathogenic/Likely pathogenic ★★ same type
TSHR p.Arg109Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
TSHR p.Arg450His Pathogenic/Likely pathogenic ★★ ⚠ same type
TSHR p.Arg519Cys Pathogenic ★★ same type
TSHR p.Arg519His Pathogenic/Likely pathogenic ★★ same type

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/tshr-p-gln90pro (accessed [today's date]).

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