Is LHCGR p.Arg554Ter (c.1660C>T) pathogenic?

LHCGR p.Arg554Ter (c.1660C>T) is classified Pathogenic/Likely pathogenic in LHCGR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-11-07). Very rare (popmax 0.000932%, nfe); Associated with disorder of sexual differentiation.

What condition is associated with LHCGR p.Arg554Ter (c.1660C>T)?

LHCGR p.Arg554Ter (c.1660C>T) is associated with disorder of sexual differentiation, Leydig cell hypoplasia, type 1 (ClinVar).

How common is LHCGR p.Arg554Ter (c.1660C>T) in the general population?

LHCGR p.Arg554Ter (c.1660C>T) is very rare (popmax 0.000932%, nfe) (gnomAD).

LHCGR p.Arg554Ter

c.1660C>T · rs121912524 · VCV14392

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Conditions

disorder of sexual differentiation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
REVEL	0.276	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,180,008 alleles

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

Overall 0.000682% 11/1,613,888 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.Arg554Ter
Coding: c.1660C>T
MANE Select: NM_000233
dbSNP: rs121912524
Type: single nucleotide variant
Location: chr2:48688137 (GRCh38)
Gene constraint: LOEUF 1.056 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.95 · 4 PDB

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

Disease context

disorder of sexual differentiation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leydig cell hypoplasia, type 1

Similar variants

LHCGR p.Arg124Ter Pathogenic/Likely pathogenic ★★ same condition
LHCGR p.Asp578Gly Pathogenic ★★ same condition
LHCGR p.Ala344Asp Uncertain significance ★★ ⚠ same condition
LHCGR p.Leu622Met Uncertain significance ★★ ⚠ same condition
LHCGR c.606-5C>T Benign/Likely benign ★★ same condition
LHCGR c.*131C>T Benign/Likely benign ★★ same condition
LHCGR c.*221G>C Benign ★★ same condition
LHCGR c.*528T>C Benign ★★ 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/lhcgr-p-arg554ter (accessed [today's date]).

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