Is FSHR p.Pro220Ser (c.658C>T) pathogenic?

FSHR p.Pro220Ser (c.658C>T) is classified Uncertain significance in FSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-18). AlphaMissense: likely pathogenic (0.8796); Very rare (popmax 0.0011%, sas).

How common is FSHR p.Pro220Ser (c.658C>T) in the general population?

FSHR p.Pro220Ser (c.658C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about FSHR p.Pro220Ser (c.658C>T)?

AlphaMissense predicts likely pathogenic (score 0.8796) — an in-silico prediction, not a clinical call.

FSHR p.Pro220Ser

c.658C>T · rs990862911 · VCV842477

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8796	likely pathogenic · top 7% in FSHR
REVEL	0.718	pathogenic-leaning
SaProt	LLR -12.57	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 12	GERP 2.7, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,066 alleles

Overall 6.2e-05% 1/1,613,342 alleles · very rare exomes 1/1,461,046 · genomes 0/152,296 · joint denominator

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.Pro220Ser
Coding: c.658C>T
MANE Select: NM_000145
dbSNP: rs990862911
Type: single nucleotide variant
Location: chr2:48982922 (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

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-pro220ser (accessed [today's date]).

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