Is LIMS2 p.Arg235Gln (c.704G>A) pathogenic?

LIMS2 p.Arg235Gln (c.704G>A) is classified Uncertain significance in LIMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-06). AlphaMissense: ambiguous (0.4819); Very rare (popmax 0.005%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2W.

What condition is associated with LIMS2 p.Arg235Gln (c.704G>A)?

LIMS2 p.Arg235Gln (c.704G>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2W (ClinVar).

How common is LIMS2 p.Arg235Gln (c.704G>A) in the general population?

LIMS2 p.Arg235Gln (c.704G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about LIMS2 p.Arg235Gln (c.704G>A)?

AlphaMissense predicts ambiguous (score 0.4819) — an in-silico prediction, not a clinical call.

LIMS2 p.Arg235Gln

c.704G>A · rs771996062 · VCV2433441

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2W

Computational evidence

Protein change
AlphaMissense	0.4819	ambiguous
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -13.19	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 36 kb · p 0.45 · regional, not allelic
Overall
CADD	29.9	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 0.005% Admixed American · 3/60,002 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00304% 49/1,613,846 alleles · very rare exomes 47/1,461,666 · genomes 2/152,180 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
European (non-Finnish)	0.00356%	28,094
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
South Asian	0.0022%	45,538
Finnishnot grpmax-eligible	0.00156%	63,938

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: LIMS2
Protein: p.Arg235Gln
Coding: c.704G>A
MANE Select: NM_001161403
dbSNP: rs771996062
Type: single nucleotide variant
Location: chr2:127640945 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.16 · 1 PDB
Residue 235: the lim zinc-binding 4 domain

Full LIMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2W — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LIMS2 p.Arg235Trp Uncertain significance ★★ ⚠ same residue
LIMS2 c.11+1287G>T Uncertain significance ★★ same condition
LIMS2 c.11+1305G>A Uncertain significance ★★ same condition
LIMS2 c.12-6769C>G Uncertain significance ★★ same condition
LIMS2 c.754-2A>G Uncertain significance ★★ same condition
LIMS2 p.Ala110Val Uncertain significance ★★ ⚠ same condition
LIMS2 p.Ala212Val Uncertain significance ★★ ⚠ same condition
LIMS2 p.Ala25Thr 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/lims2-p-arg235gln (accessed [today's date]).

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