Is LIM2 p.Val112Ile (c.334G>A) pathogenic?

LIM2 p.Val112Ile (c.334G>A) is classified Uncertain significance in LIM2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0929); Rare (popmax 0.214%, mid); Associated with cataract 19 multiple types.

What condition is associated with LIM2 p.Val112Ile (c.334G>A)?

LIM2 p.Val112Ile (c.334G>A) is associated with cataract 19 multiple types (ClinVar).

How common is LIM2 p.Val112Ile (c.334G>A) in the general population?

LIM2 p.Val112Ile (c.334G>A) is rare (popmax 0.214%, mid) (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.Val112Ile (c.334G>A)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

LIM2 p.Val112Ile

c.334G>A · rs142030761 · VCV329972

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.214%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cataract 19 multiple types

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.368	indeterminate
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.35	GERP 0.054
Regional constraint	o/e 0.94	unconstrained · MANE · 7,239 bp · p 0.39 · regional, not allelic
Overall
CADD	16.15	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.214% Middle Eastern · 13/6,082 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.1%

Overall 0.0266% 430/1,613,712 alleles · rare exomes 408/1,461,840 · genomes 22/151,872 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.214%	468
European (non-Finnish)	0.0339%	2,950
Remaining individualsnot grpmax-eligible	0.0144%	6,942
East Asian	0.00669%	14,954
Admixed American	0.00334%	29,978
Finnishnot grpmax-eligible	0.00156%	63,950
African / African-American	0.00134%	74,786
South Asian	0.0011%	91,078

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.Val112Ile
Coding: c.334G>A
MANE Select: NM_001161748
dbSNP: rs142030761
Type: single nucleotide variant
Location: chr19:51380631 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.11 · 1 PDB
Residue 112: an α-helix

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.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
LIM2 p.Arg167Gln Uncertain significance ★★ ⚠ same condition
LIM2 p.Arg168Cys 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-val112ile (accessed [today's date]).

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