Is LIM2 p.Arg94His (c.281G>A) pathogenic?

LIM2 p.Arg94His (c.281G>A) is classified Uncertain significance in LIM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0347%, afr); Associated with cataract 19 multiple types.

What condition is associated with LIM2 p.Arg94His (c.281G>A)?

LIM2 p.Arg94His (c.281G>A) is associated with cataract 19 multiple types (ClinVar).

How common is LIM2 p.Arg94His (c.281G>A) in the general population?

LIM2 p.Arg94His (c.281G>A) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

How is Early onset non-syndromic cataract inherited?

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

What do computational predictors say about LIM2 p.Arg94His (c.281G>A)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

LIM2 p.Arg94His

c.281G>A · rs770425768 · VCV1345456

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 19 multiple types

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.692	pathogenic-leaning
SaProt	LLR -7.11	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,239 bp · p 0.39 · regional, not allelic
Overall
CADD	25.0	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 0.0347% African / African-American · 26/74,930 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.0103% 166/1,613,832 alleles · ultra-rare exomes 140/1,461,832 · genomes 26/152,000 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,882
Admixed American	0.0183%	5,452
European (non-Finnish)	0.01%	10,000
Remaining individualsnot grpmax-eligible	0.008%	12,496
East Asian	0.00669%	14,951
South Asian	0.0022%	45,538
Finnishnot grpmax-eligible	0.00156%	63,982

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: LIM2
Protein: p.Arg94His
Coding: c.281G>A
MANE Select: NM_001161748
dbSNP: rs770425768
Type: single nucleotide variant
Location: chr19:51382462 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.11 · 1 PDB
Residue 94: a β-strand

Full LIM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 19 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

LIM2 p.Arg94Cys Uncertain significance ★ ⚠ same residue
LIM2 p.Arg94Ser Uncertain significance ★ ⚠ same residue
LIM2 p.Arg130Cys Pathogenic/Likely pathogenic ★★ same condition
LIM2 c.175+113G>C Uncertain significance ★★ same condition
LIM2 c.175+28G>A Uncertain significance ★★ same condition
LIM2 p.Ala153Thr Uncertain significance ★★ ⚠ same condition
LIM2 p.Arg129Cys Uncertain significance ★★ ⚠ same condition
LIM2 p.Arg162Trp 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/lim2-p-arg94his (accessed [today's date]).

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