Is LHB p.Pro44= (c.132A>C) pathogenic?

LHB p.Pro44= (c.132A>C) is classified Benign in LHB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 66.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hypogonadotropic hypogonadism 23 with or without anosmia.

What condition is associated with LHB p.Pro44= (c.132A>C)?

LHB p.Pro44= (c.132A>C) is associated with hypogonadotropic hypogonadism 23 with or without anosmia (ClinVar).

LHB p.Pro44=

Q: How common is LHB p.Pro44= (c.132A>C) in the general population?

LHB p.Pro44= (c.132A>C) is common (popmax 66.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.132A>C · rs1056914 · VCV518302

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 66.2%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hypogonadotropic hypogonadism 23 with or without anosmia

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 -15
Overall
CADD	0.016	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 66.2% African / African-American · 49,005/74,040 alleles

Filtering AF 65.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 65.5%

Overall 50.8% 811,794/1,597,094 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	66.2%	2
Admixed American	64%	2
Amishnot grpmax-eligible	54.3%	2
Middle Eastern	53.1%	2
Ashkenazi Jewishnot grpmax-eligible	50.8%	2
Remaining individualsnot grpmax-eligible	50.6%	2
South Asian	50.5%	2
European (non-Finnish)	50.2%	2
Finnishnot grpmax-eligible	48.7%	2
East Asian	28.3%	4

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: LHB
Protein: p.Pro44=
Coding: c.132A>C
MANE Select: NM_000894
dbSNP: rs1056914
Type: single nucleotide variant
Location: chr19:49016598 (GRCh38)
Gene constraint: LOEUF 1.603 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.33
Residue 44: a disulfide bond

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

Disease context

hypogonadotropic hypogonadism 23 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leydig cell hypoplasia (Orphanet):

Onset: Neonatal

Similar variants

LHB p.Val96Met Uncertain significance ★★ ⚠ same condition
LHB c.15+9A>G Benign ★★ same condition
LHB c.16-26T>C Benign ★★ same condition
LHB c.183+11T>C Benign ★★ same condition
LHB p.Gly122Ser Likely benign ★★ same condition
LHB p.Gly95= Benign ★★ same condition
LHB p.Thr78Asn Benign/Likely benign ★★ ⚠ same condition
LHB p.Val38= 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/lhb-p-pro44 (accessed [today's date]).

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