Is FSHR p.Phe629Cys (c.1886T>G) pathogenic?

FSHR p.Phe629Cys (c.1886T>G) is classified Uncertain significance in FSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). AlphaMissense: likely benign (0.2355); Very rare (popmax 0.000932%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FSHR p.Phe629Cys (c.1886T>G)?

FSHR p.Phe629Cys (c.1886T>G) is associated with Inborn genetic diseases (ClinVar).

How common is FSHR p.Phe629Cys (c.1886T>G) in the general population?

FSHR p.Phe629Cys (c.1886T>G) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about FSHR p.Phe629Cys (c.1886T>G)?

AlphaMissense predicts likely benign (score 0.2355) — an in-silico prediction, not a clinical call.

FSHR p.Phe629Cys

c.1886T>G · VCV3517497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2355 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2355	likely benign
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -7.18	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 192 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	27.6	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 0.000932% European (non-Finnish) · 11/1,180,028 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000867% 14/1,614,066 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,830
European (non-Finnish)grpmax	0.000932%	107,275

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe629Cys
Coding: c.1886T>G
MANE Select: NM_000145
Type: single nucleotide variant
Location: chr2:48962935 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FSHR p.Phe629Ile Uncertain significance ★ ⚠ same residue
FSHR p.Arg557Trp Uncertain significance ★★ ⚠ same condition
FSHR p.Asp358Val Uncertain significance ★★ ⚠ same condition
FSHR p.Ile230Val Uncertain significance ★★ ⚠ same condition
FSHR p.Met532Ile Uncertain significance ★★ ⚠ same condition
FSHR p.Thr329Lys Uncertain significance ★★ ⚠ same condition
FSHR p.Ala352Val Uncertain significance ★ ⚠ same condition
FSHR p.Ala444Val 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-phe629cys (accessed [today's date]).

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