Is FSHR p.Glu466Lys (c.1396G>A) pathogenic?

FSHR p.Glu466Lys (c.1396G>A) is classified Likely pathogenic in FSHR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-01). AlphaMissense: likely pathogenic (0.7593); Absent from gnomAD v4.1; Associated with Genetic non-acquired premature ovarian failure.

What condition is associated with FSHR p.Glu466Lys (c.1396G>A)?

FSHR p.Glu466Lys (c.1396G>A) is associated with Genetic non-acquired premature ovarian failure (ClinVar).

How common is FSHR p.Glu466Lys (c.1396G>A) in the general population?

FSHR p.Glu466Lys (c.1396G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FSHR p.Glu466Lys (c.1396G>A)?

AlphaMissense predicts likely pathogenic (score 0.7593) — an in-silico prediction, not a clinical call.

FSHR p.Glu466Lys

c.1396G>A · rs2103991776 · VCV1256019

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7593 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Genetic non-acquired premature ovarian failure

Computational evidence

Protein change
AlphaMissense	0.7593	likely pathogenic ✓ concordant with ClinVar
REVEL	0.761	pathogenic-leaning
SaProt	LLR -14.86	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 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	29.4	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: FSHR
Protein: p.Glu466Lys
Coding: c.1396G>A
MANE Select: NM_000145
dbSNP: rs2103991776
Type: single nucleotide variant
Location: chr2:48963425 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 466: an α-helix; a disulfide bond

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

Disease context

Genetic non-acquired premature ovarian failure — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FSHR p.Gln117Ter Pathogenic same condition
FSHR p.Ile588Thr Likely pathogenic same condition
FSHR p.Leu125Arg Likely pathogenic same condition
FSHR p.Ser295Phe Likely pathogenic ⚠ same condition
FSHR p.Thr228Ile Likely pathogenic same condition
FSHR p.Asn560fs Pathogenic same condition
FSHR p.Arg229Gly Uncertain significance ★★ ⚠ same type
FSHR p.Arg557Trp Uncertain significance ★★ ⚠ 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/fshr-p-glu466lys (accessed [today's date]).

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