Is FSHR p.Leu526= (c.1576T>C) pathogenic?

FSHR p.Leu526= (c.1576T>C) is classified Uncertain significance in FSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Very rare (popmax 0.01%, amr); Associated with ovarian hyperstimulation syndrome.

What condition is associated with FSHR p.Leu526= (c.1576T>C)?

FSHR p.Leu526= (c.1576T>C) is associated with ovarian hyperstimulation syndrome, ovarian dysgenesis 1 (ClinVar).

How common is FSHR p.Leu526= (c.1576T>C) in the general population?

FSHR p.Leu526= (c.1576T>C) is very rare (popmax 0.01%, amr) (gnomAD).

How is Ovarian hyperstimulation syndrome inherited?

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

FSHR p.Leu526=

c.1576T>C · rs138281715 · VCV336481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

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 0.28	GERP -4.6, phastCons 0.3
Overall
CADD	1.344	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,002 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00142% 23/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,000
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-American	0.00133%	74,942
European (non-Finnish)	0.00119%	84,289

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.Leu526=
Coding: c.1576T>C
MANE Select: NM_000145
dbSNP: rs138281715
Type: single nucleotide variant
Location: chr2:48963245 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 526: an α-helix

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.Lys133= Uncertain significance ★★ same condition
FSHR p.Met532Ile 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-leu526 (accessed [today's date]).

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