Is FSHR p.Lys133= (c.399G>A) pathogenic?

FSHR p.Lys133= (c.399G>A) is classified Uncertain significance in FSHR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-02-09). Rare (popmax 0.314%, afr); Associated with ovarian hyperstimulation syndrome.

What condition is associated with FSHR p.Lys133= (c.399G>A)?

FSHR p.Lys133= (c.399G>A) is associated with ovarian hyperstimulation syndrome, ovarian dysgenesis 1 (ClinVar).

How common is FSHR p.Lys133= (c.399G>A) in the general population?

FSHR p.Lys133= (c.399G>A) is rare (popmax 0.314%, afr) (gnomAD).

How is Ovarian hyperstimulation syndrome inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

FSHR p.Lys133=

c.399G>A · rs148815172 · VCV595880

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.314%, afr)

Conditions

ovarian hyperstimulation syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -0.84, phastCons 1
Overall
CADD	8.583	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.314% African / African-American · 235/74,938 alleles

Filtering AF 0.281% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.268%

Overall 0.0235% 379/1,611,548 alleles · rare exomes 175/1,459,318 · genomes 204/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.314%	319
Admixed American	0.157%	638
Remaining individualsnot grpmax-eligible	0.0705%	1,419
Middle Eastern	0.0165%	6,058
European (non-Finnish)	0.000425%	235,560

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: FSHR
Protein: p.Lys133=
Coding: c.399G>A
MANE Select: NM_000145
dbSNP: rs148815172
Type: single nucleotide variant
Location: chr2:48990613 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB

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

Disease context

ovarian hyperstimulation syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ovarian dysgenesis 1

For Ovarian hyperstimulation syndrome (Orphanet):

Inheritance: Not applicable
Onset: Adolescent, Adult

Similar variants

FSHR p.Arg229Gly Uncertain significance ★★ ⚠ same condition
FSHR p.Arg557Trp Uncertain significance ★★ ⚠ same condition
FSHR p.Glu300Lys Uncertain significance ★★ ⚠ same condition
FSHR p.Glu319Gly Uncertain significance ★★ ⚠ same condition
FSHR p.Ile230Val Uncertain significance ★★ ⚠ same condition
FSHR p.Ile382Thr Uncertain significance ★★ ⚠ same condition
FSHR p.Met532Ile Uncertain significance ★★ ⚠ same condition
FSHR p.Pro45= Uncertain significance ★★ 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/fshr-p-lys133 (accessed [today's date]).

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