Is LHB p.Pro103Ala (c.307C>G) pathogenic?

LHB p.Pro103Ala (c.307C>G) is classified Uncertain significance in LHB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-27). AlphaMissense: likely benign (0.2226); Very rare (popmax 8.47e-05%, nfe).

How common is LHB p.Pro103Ala (c.307C>G) in the general population?

LHB p.Pro103Ala (c.307C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about LHB p.Pro103Ala (c.307C>G)?

AlphaMissense predicts likely benign (score 0.2226) — an in-silico prediction, not a clinical call.

LHB p.Pro103Ala

c.307C>G · VCV3538075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2226 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2226	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -12.13	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.6	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 1,010 bp · p 0.34 · regional, not allelic
Overall
CADD	15.58	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 8.47e-05% European (non-Finnish) · 1/1,179,968 alleles

Overall 6.2e-05% 1/1,612,686 alleles · very rare exomes 1/1,460,334 · genomes 0/152,352 · joint denominator

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.Pro103Ala
Coding: c.307C>G
MANE Select: NM_000894
Type: single nucleotide variant
Location: chr19:49016187 (GRCh38)
Gene constraint: LOEUF 1.603 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.33

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

Similar variants

LHB p.His30Arg Uncertain significance ★★ ⚠ same type
LHB p.Pro59Ala Uncertain significance ★★ ⚠ same type
LHB p.Pro93Arg Uncertain significance ★★ ⚠ same type
LHB p.Val96Met Uncertain significance ★★ ⚠ same type
LHB c.15+72C>A Likely benign ★★ same type
LHB c.15+9A>G Benign ★★ same type
LHB c.16-104G>C Likely benign ★★ same type
LHB c.16-105G>A Benign ★★ same type

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-pro103ala (accessed [today's date]).

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