Is FSHR p.Phe629Ile (c.1885T>A) pathogenic?

FSHR p.Phe629Ile (c.1885T>A) is classified Uncertain significance in FSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: ambiguous (0.4205); Ultra-rare (popmax 0.0538%, sas); Associated with Inborn genetic diseases.

What condition is associated with FSHR p.Phe629Ile (c.1885T>A)?

FSHR p.Phe629Ile (c.1885T>A) is associated with Inborn genetic diseases (ClinVar).

How common is FSHR p.Phe629Ile (c.1885T>A) in the general population?

FSHR p.Phe629Ile (c.1885T>A) is ultra-rare (popmax 0.0538%, sas) (gnomAD).

What do computational predictors say about FSHR p.Phe629Ile (c.1885T>A)?

AlphaMissense predicts ambiguous (score 0.4205) — an in-silico prediction, not a clinical call.

FSHR p.Phe629Ile

c.1885T>A · rs535994306 · VCV3097192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4205 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0538%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4205	ambiguous
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -7.44	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
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	26.0	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 0.0538% South Asian · 49/91,082 alleles

Filtering AF 0.0418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0375%

Overall 0.0031% 50/1,614,170 alleles · ultra-rare exomes 48/1,461,862 · genomes 2/152,308 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0538%	1,859
European (non-Finnish)	8.47e-05%	1,180,016

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.Phe629Ile
Coding: c.1885T>A
MANE Select: NM_000145
dbSNP: rs535994306
Type: single nucleotide variant
Location: chr2:48962936 (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.Phe629Cys 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-phe629ile (accessed [today's date]).

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