Is LIMS2 p.Pro97Ser (c.289C>T) pathogenic?

LIMS2 p.Pro97Ser (c.289C>T) is classified Uncertain significance in LIMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.7079); Ultra-rare (popmax 0.0188%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2W.

What condition is associated with LIMS2 p.Pro97Ser (c.289C>T)?

LIMS2 p.Pro97Ser (c.289C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2W (ClinVar).

How common is LIMS2 p.Pro97Ser (c.289C>T) in the general population?

LIMS2 p.Pro97Ser (c.289C>T) is ultra-rare (popmax 0.0188%, nfe) (gnomAD).

What do computational predictors say about LIMS2 p.Pro97Ser (c.289C>T)?

AlphaMissense predicts likely pathogenic (score 0.7079) — an in-silico prediction, not a clinical call.

LIMS2 p.Pro97Ser

c.289C>T · rs368536679 · VCV475546

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7079 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2W

Computational evidence

Protein change
AlphaMissense	0.7079	likely pathogenic
REVEL	0.751	pathogenic-leaning
SaProt	LLR -13.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 36 kb · p 0.45 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0188% European (non-Finnish) · 222/1,180,020 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.0147% 238/1,614,028 alleles · ultra-rare exomes 230/1,461,808 · genomes 8/152,220 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0188%	5,315
Remaining individualsnot grpmax-eligible	0.0128%	7,811
Finnishnot grpmax-eligible	0.00937%	10,669
African / African-American	0.00267%	37,467

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.Pro97Ser
Coding: c.289C>T
MANE Select: NM_001161403
dbSNP: rs368536679
Type: single nucleotide variant
Location: chr2:127654494 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.16 · 1 PDB
Residue 97: a UniProt-annotated variant site (in mdrcmtt; uncertain significance); the lim zinc-binding 2 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.Pro97Leu Uncertain significance ★★ ⚠ same residue
LIMS2 p.Pro97= Benign ★ 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

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-pro97ser (accessed [today's date]).

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