Is FSHR p.Leu8Phe (c.24G>T) pathogenic?

FSHR p.Leu8Phe (c.24G>T) is classified Conflicting classifications of pathogenicity in FSHR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0587); Low-frequency (popmax 1.73%, eas); Associated with ovarian dysgenesis 1.

What condition is associated with FSHR p.Leu8Phe (c.24G>T)?

FSHR p.Leu8Phe (c.24G>T) is associated with ovarian dysgenesis 1, ovarian hyperstimulation syndrome (ClinVar).

How common is FSHR p.Leu8Phe (c.24G>T) in the general population?

FSHR p.Leu8Phe (c.24G>T) is low-frequency (popmax 1.73%, eas) (gnomAD).

What do computational predictors say about FSHR p.Leu8Phe (c.24G>T)?

AlphaMissense predicts likely benign (score 0.0587) — an in-silico prediction, not a clinical call.

FSHR p.Leu8Phe

c.24G>T · rs115030945 · VCV255348

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0587 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.73%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian dysgenesis 1

Computational evidence

Protein change
AlphaMissense	0.0587	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.2	GERP 0.2, phastCons 0.97
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	16.05	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 1.73% East Asian · 775/44,826 alleles

Filtering AF 1.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.59%

Overall 0.0499% 804/1,612,820 alleles · low-frequency exomes 725/1,460,672 · genomes 79/152,148 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.73%	58
Remaining individualsnot grpmax-eligible	0.0337%	2,971
Middle Eastern	0.0192%	5,208
South Asian	0.00549%	18,201
Admixed American	0.00333%	30,003

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.Leu8Phe
Coding: c.24G>T
MANE Select: NM_000145
dbSNP: rs115030945
Type: single nucleotide variant
Location: chr2:49154394 (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 dysgenesis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ovarian hyperstimulation syndrome

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-leu8phe (accessed [today's date]).

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