Is FSHR p.Val556Leu (c.1666G>C) pathogenic?

FSHR p.Val556Leu (c.1666G>C) is classified Uncertain significance in FSHR (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.5479); Absent from gnomAD v4.1; Associated with ovarian dysgenesis 1.

What condition is associated with FSHR p.Val556Leu (c.1666G>C)?

FSHR p.Val556Leu (c.1666G>C) is associated with ovarian dysgenesis 1 (ClinVar).

How common is FSHR p.Val556Leu (c.1666G>C) in the general population?

FSHR p.Val556Leu (c.1666G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FSHR p.Val556Leu (c.1666G>C)?

AlphaMissense predicts ambiguous (score 0.5479) — an in-silico prediction, not a clinical call.

FSHR p.Val556Leu

c.1666G>C · VCV3381985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5479 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

ovarian dysgenesis 1

Computational evidence

Protein change
AlphaMissense	0.5479	ambiguous
REVEL	0.313	indeterminate
SaProt	LLR -7.07	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	25.7	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.Val556Leu
Coding: c.1666G>C
MANE Select: NM_000145
Type: single nucleotide variant
Location: chr2:48963155 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 556: an α-helix

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

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-val556leu (accessed [today's date]).

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