Is LBR p.Pro561Ala (c.1681C>G) pathogenic?

LBR p.Pro561Ala (c.1681C>G) is classified Uncertain significance in LBR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-28). AlphaMissense: likely benign (0.1818); Very rare (popmax 0.004%, afr).

How common is LBR p.Pro561Ala (c.1681C>G) in the general population?

LBR p.Pro561Ala (c.1681C>G) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about LBR p.Pro561Ala (c.1681C>G)?

AlphaMissense predicts likely benign (score 0.1818) — an in-silico prediction, not a clinical call.

LBR p.Pro561Ala

c.1681C>G · rs192296368 · VCV1370940

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1818	likely benign
REVEL	0.667	pathogenic-leaning
SaProt	LLR -13.18	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	24.7	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 0.004% African / African-American · 3/75,028 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000248% 4/1,614,048 alleles · very rare exomes 1/1,461,764 · genomes 3/152,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,009
European (non-Finnish)	8.47e-05%	1,180,020

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: LBR
Protein: p.Pro561Ala
Coding: c.1681C>G
MANE Select: NM_002296
dbSNP: rs192296368
Type: single nucleotide variant
Location: chr1:225404410 (GRCh38)
Gene constraint: LOEUF 0.499 · pLI 0.97 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.89 · 1 PDB
Residue 561: a UniProt-annotated variant site (in skpha)

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

Similar variants

LBR p.Pro561= Likely benign ★ same residue
LBR c.367-2A>C Pathogenic/Likely pathogenic ★★ same type
LBR p.Arg512Gln Pathogenic/Likely pathogenic ★★ same type
LBR p.Arg583Gln Pathogenic ★★ same type
LBR p.Arg586His Pathogenic/Likely pathogenic ★★ same type
LBR p.Asn547Asp Pathogenic/Likely pathogenic ★★ same type
LBR p.Asn547Ser Pathogenic/Likely pathogenic ★★ same type
LBR c.*1586G>A Uncertain significance ★★ 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/lbr-p-pro561ala (accessed [today's date]).

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