Is TSHR p.Val656Ile (c.1966G>A) pathogenic?

TSHR p.Val656Ile (c.1966G>A) is classified Likely pathogenic in TSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-30). AlphaMissense: likely benign (0.1171); Absent from gnomAD v4.1; Associated with familial hyperthyroidism due to mutations in TSH receptor.

What condition is associated with TSHR p.Val656Ile (c.1966G>A)?

TSHR p.Val656Ile (c.1966G>A) is associated with familial hyperthyroidism due to mutations in TSH receptor (ClinVar).

How common is TSHR p.Val656Ile (c.1966G>A) in the general population?

TSHR p.Val656Ile (c.1966G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSHR p.Val656Ile (c.1966G>A)?

AlphaMissense predicts likely benign (score 0.1171) — an in-silico prediction, not a clinical call.

TSHR p.Val656Ile

Q: How is Familial hyperthyroidism due to mutations in TSH receptor inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1966G>A · rs2140113373 · VCV2663912

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1171 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial hyperthyroidism due to mutations in TSH receptor

Computational evidence

Protein change
AlphaMissense	0.1171	likely benign ⚠ discordant with ClinVar
REVEL	0.402	indeterminate
SaProt	LLR -8.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 4.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	21.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSHR
Protein: p.Val656Ile
Coding: c.1966G>A
MANE Select: NM_000369
dbSNP: rs2140113373
Type: single nucleotide variant
Location: chr14:81144024 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 9 PDB
Residue 656: a UniProt-annotated variant site (found in toxic thyroid nodules); an α-helix

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

Disease context

familial hyperthyroidism due to mutations in TSH receptor — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hyperthyroidism due to mutations in TSH receptor (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

TSHR c.881+1G>T Pathogenic/Likely pathogenic ★★ same condition
TSHR p.Ala553Thr Pathogenic/Likely pathogenic ★★ same condition
TSHR p.Arg109Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
TSHR p.Arg450His Pathogenic/Likely pathogenic ★★ ⚠ same condition
TSHR p.Arg519His Pathogenic/Likely pathogenic ★★ same condition
TSHR p.Cys390Trp Pathogenic/Likely pathogenic ★★ same condition
TSHR p.Gly132Arg Likely pathogenic ★★ same condition
TSHR p.Pro162Ala 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/tshr-p-val656ile (accessed [today's date]).

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