Is TSHR p.Val424Phe (c.1270G>T) pathogenic?

TSHR p.Val424Phe (c.1270G>T) is classified Uncertain significance in TSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-06). AlphaMissense: likely pathogenic (0.6516); Very rare (popmax 0.00167%, amr).

How common is TSHR p.Val424Phe (c.1270G>T) in the general population?

TSHR p.Val424Phe (c.1270G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TSHR p.Val424Phe (c.1270G>T)?

AlphaMissense predicts likely pathogenic (score 0.6516) — an in-silico prediction, not a clinical call.

TSHR p.Val424Phe

c.1270G>T · VCV3336132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6516 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6516	likely pathogenic
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -10.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 3.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,006 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000805% 13/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0141%	7,115
Admixed Americangrpmax	0.00167%	60,006
European (non-Finnish)	0.000254%	393,349

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val424Phe
Coding: c.1270G>T
MANE Select: NM_000369
Type: single nucleotide variant
Location: chr14:81143328 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 9 PDB
Residue 424: an α-helix

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

Similar variants

TSHR p.Val424= Likely benign ★ 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-val424phe (accessed [today's date]).

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