Is FSHR p.Gly446Ser (c.1336G>A) pathogenic?

FSHR p.Gly446Ser (c.1336G>A) is classified Likely pathogenic in FSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2014-06-04). AlphaMissense: likely pathogenic (0.8815); Very rare (popmax 0.00161%, nfe).

How common is FSHR p.Gly446Ser (c.1336G>A) in the general population?

FSHR p.Gly446Ser (c.1336G>A) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about FSHR p.Gly446Ser (c.1336G>A)?

AlphaMissense predicts likely pathogenic (score 0.8815) — an in-silico prediction, not a clinical call.

FSHR p.Gly446Ser

c.1336G>A · rs371482817 · VCV988344

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8815	likely pathogenic ✓ concordant with ClinVar · top 7% in FSHR
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -14.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	28.4	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 0.00161% European (non-Finnish) · 19/1,180,010 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0013% 19/1,461,828 alleles · very rare

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.Gly446Ser
Coding: c.1336G>A
MANE Select: NM_000145
dbSNP: rs371482817
Type: single nucleotide variant
Location: chr2:48963485 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.87 · 5 PDB
Residue 446: an α-helix; a disulfide bond

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

Similar variants

FSHR p.Arg229Gly Uncertain significance ★★ ⚠ same type
FSHR p.Arg557Trp Uncertain significance ★★ ⚠ same type
FSHR p.Asp358Val Uncertain significance ★★ ⚠ same type
FSHR p.Glu300Lys Uncertain significance ★★ ⚠ same type
FSHR p.Glu319Gly Uncertain significance ★★ ⚠ same type
FSHR p.Ile230Val Uncertain significance ★★ ⚠ same type
FSHR p.Ile382Thr Uncertain significance ★★ ⚠ same type
FSHR p.Lys133= Uncertain significance ★★ same type

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-gly446ser (accessed [today's date]).

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