Is FSHR p.Val166Leu (c.496G>T) pathogenic?

FSHR p.Val166Leu (c.496G>T) is classified Conflicting classifications of pathogenicity in FSHR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0737); Ultra-rare (popmax 0.0342%, nfe); Associated with ovarian hyperstimulation syndrome.

What condition is associated with FSHR p.Val166Leu (c.496G>T)?

FSHR p.Val166Leu (c.496G>T) is associated with ovarian hyperstimulation syndrome, ovarian dysgenesis 1 (ClinVar).

How common is FSHR p.Val166Leu (c.496G>T) in the general population?

FSHR p.Val166Leu (c.496G>T) is ultra-rare (popmax 0.0342%, nfe) (gnomAD).

How is Ovarian hyperstimulation syndrome inherited?

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

What do computational predictors say about FSHR p.Val166Leu (c.496G>T)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

FSHR p.Val166Leu

c.496G>T · rs142383710 · VCV898896

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0342%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ovarian hyperstimulation syndrome

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.26	acceptor loss, 49 bp away · masked 0 · deltas
Pangolin	Δ0.37	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -3.3	GERP -5.3
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	0.508	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

Grpmax group 0.0342% European (non-Finnish) · 404/1,179,910 alleles

Filtering AF 0.0315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0304%

Overall 0.0273% 441/1,613,934 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0342%	2,921
Remaining individualsnot grpmax-eligible	0.0336%	2,976
Middle Eastern	0.033%	3,031
Admixed American	0.00833%	12,003
African / African-American	0.00667%	15,004
Finnishnot grpmax-eligible	0.00625%	15,999

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.Val166Leu
Coding: c.496G>T
MANE Select: NM_000145
dbSNP: rs142383710
Type: single nucleotide variant
Location: chr2:48989005 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 166: a turn

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-val166leu (accessed [today's date]).

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