Is LIMS2 p.Phe253= (c.759C>T) pathogenic?

LIMS2 p.Phe253= (c.759C>T) is classified Likely benign in LIMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-09). Ultra-rare (popmax 0.0307%, afr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2W.

What condition is associated with LIMS2 p.Phe253= (c.759C>T)?

LIMS2 p.Phe253= (c.759C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2W (ClinVar).

How common is LIMS2 p.Phe253= (c.759C>T) in the general population?

LIMS2 p.Phe253= (c.759C>T) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

LIMS2 p.Phe253=

c.759C>T · rs370106270 · VCV1550704

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2W

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.293	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.085	GERP -0.25, phastCons 0.1
Overall
CADD	10.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0307% African / African-American · 23/74,918 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00347% 56/1,612,720 alleles · ultra-rare exomes 44/1,460,520 · genomes 12/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,257
European (non-Finnish)	0.00263%	38,062
Remaining individualsnot grpmax-eligible	0.0016%	62,442
Finnishnot grpmax-eligible	0.00158%	63,192

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.Phe253=
Coding: c.759C>T
MANE Select: NM_001161403
dbSNP: rs370106270
Type: single nucleotide variant
Location: chr2:127640313 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.16 · 1 PDB
Residue 253: 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 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
LIMS2 p.Ala44Thr 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-phe253 (accessed [today's date]).

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