Is LHCGR p.Phe641Cys (c.1922T>G) pathogenic?

LHCGR p.Phe641Cys (c.1922T>G) is classified Uncertain significance in LHCGR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely benign (0.1299); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with LHCGR p.Phe641Cys (c.1922T>G)?

LHCGR p.Phe641Cys (c.1922T>G) is associated with Inborn genetic diseases (ClinVar).

How common is LHCGR p.Phe641Cys (c.1922T>G) in the general population?

LHCGR p.Phe641Cys (c.1922T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about LHCGR p.Phe641Cys (c.1922T>G)?

AlphaMissense predicts likely benign (score 0.1299) — an in-silico prediction, not a clinical call.

LHCGR p.Phe641Cys

c.1922T>G · VCV4623632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1299 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1299	likely benign
REVEL	0.681	pathogenic-leaning
SaProt	LLR -7.03	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 8.1	GERP 1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 68 kb · p 0.37 · regional, not allelic
Overall
CADD	23.0	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 0.00133% African / African-American · 1/74,922 alleles

Overall 0.000657% 1/152,176 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: LHCGR
Protein: p.Phe641Cys
Coding: c.1922T>G
MANE Select: NM_000233
Type: single nucleotide variant
Location: chr2:48687875 (GRCh38)
Gene constraint: LOEUF 1.056 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.95 · 4 PDB
Residue 641: an α-helix

Full LHCGR 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

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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/lhcgr-p-phe641cys (accessed [today's date]).

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