Is LHCGR p.Asp355= (c.1065T>C) pathogenic?

LHCGR p.Asp355= (c.1065T>C) is classified Benign in LHCGR (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Common (popmax 93.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with familial male-limited precocious puberty.

What condition is associated with LHCGR p.Asp355= (c.1065T>C)?

LHCGR p.Asp355= (c.1065T>C) is associated with familial male-limited precocious puberty, Leydig cell hypoplasia, type 1 (ClinVar).

LHCGR p.Asp355=

Q: How common is LHCGR p.Asp355= (c.1065T>C) in the general population?

LHCGR p.Asp355= (c.1065T>C) is common (popmax 93.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Familial peripheral male-limited precocious puberty inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1065T>C · rs11125179 · VCV255607

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 93.5%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

familial male-limited precocious puberty

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -4.3, phastCons 0.13
Overall
CADD	3.312	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 93.5% East Asian · 41,941/44,864 alleles

Filtering AF 92.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 92.4%

Overall 58.5% 943,082/1,613,476 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	93.5%	1
Middle Eastern	69.3%	1
Admixed American	68.2%	1
Ashkenazi Jewishnot grpmax-eligible	66.2%	2
Remaining individualsnot grpmax-eligible	60.3%	2
South Asian	60%	2
European (non-Finnish)	58%	2
Finnishnot grpmax-eligible	57.4%	2
Amishnot grpmax-eligible	49.3%	2
African / African-American	31%	3

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.Asp355=
Coding: c.1065T>C
MANE Select: NM_000233
dbSNP: rs11125179
Type: single nucleotide variant
Location: chr2:48688732 (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

familial male-limited precocious puberty — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leydig cell hypoplasia, type 1

For Familial peripheral male-limited precocious puberty (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

LHCGR p.Arg124Ter Pathogenic/Likely pathogenic ★★ same condition
LHCGR p.Arg554Ter Pathogenic/Likely pathogenic ★★ same condition
LHCGR p.Asp564Gly Pathogenic ★★ same condition
LHCGR p.Asp578Gly Pathogenic ★★ ⚠ same condition
LHCGR p.Ile542Leu Pathogenic ★★ ⚠ same condition
LHCGR p.Thr577Ile Pathogenic/Likely pathogenic ★★ same condition
LHCGR p.Ala344Asp Uncertain significance ★★ ⚠ same condition
LHCGR p.Leu622Met 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/lhcgr-p-asp355 (accessed [today's date]).

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