Is LIMA1 p.Arg589Pro (c.1766G>C) pathogenic?

LIMA1 p.Arg589Pro (c.1766G>C) is classified Uncertain significance in LIMA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.9647); Ultra-rare (popmax 0.0122%, sas).

How common is LIMA1 p.Arg589Pro (c.1766G>C) in the general population?

LIMA1 p.Arg589Pro (c.1766G>C) is ultra-rare (popmax 0.0122%, sas) (gnomAD).

What do computational predictors say about LIMA1 p.Arg589Pro (c.1766G>C)?

AlphaMissense predicts likely pathogenic (score 0.9647) — an in-silico prediction, not a clinical call.

LIMA1 p.Arg589Pro

c.1766G>C · VCV4047316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9647 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9647	likely pathogenic · top 5% in LIMA1
REVEL	0.612	indeterminate
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 72 kb · p 4.7e-05 · regional, not allelic
Overall
CADD	28.1	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 0.0122% South Asian · 11/90,488 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.000745% 12/1,611,408 alleles · ultra-rare exomes 11/1,459,098 · genomes 1/152,310 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0122%	8,226
Remaining individualsnot grpmax-eligible	0.0016%	62,328

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: LIMA1
Protein: p.Arg589Pro
Coding: c.1766G>C
MANE Select: NM_016357
Type: single nucleotide variant
Location: chr12:50177578 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.12 · 1 PDB
Residue 589: the 'disordered' region

Full LIMA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LIMA1 p.Ala113Gly Uncertain significance ★ ⚠ same type
LIMA1 p.Ala136Val Uncertain significance ★ ⚠ same type
LIMA1 p.Ala183Asp Uncertain significance ★ ⚠ same type
LIMA1 p.Ala214Ser Uncertain significance ★ ⚠ same type
LIMA1 p.Ala367Val Uncertain significance ★ ⚠ same type
LIMA1 p.Ala479Val Uncertain significance ★ ⚠ same type
LIMA1 p.Ala531Thr Uncertain significance ★ ⚠ same type
LIMA1 p.Arg141Gln 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/lima1-p-arg589pro (accessed [today's date]).

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