Is LMX1B p.Arg221Ter (c.661C>T) pathogenic?

LMX1B p.Arg221Ter (c.661C>T) is classified Pathogenic in LMX1B (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-08). Absent from gnomAD v4.1; Associated with nail-patella syndrome.

What condition is associated with LMX1B p.Arg221Ter (c.661C>T)?

LMX1B p.Arg221Ter (c.661C>T) is associated with nail-patella syndrome (ClinVar).

How common is LMX1B p.Arg221Ter (c.661C>T) in the general population?

LMX1B p.Arg221Ter (c.661C>T) is absent from gnomAD v4.1 (gnomAD).

LMX1B p.Arg221Ter

c.661C>T · rs121909487 · VCV7001

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,611,432)

Conditions

nail-patella syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 4 of 8
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.92, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,611,432). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: LMX1B
Protein: p.Arg221Ter
Coding: c.661C>T
MANE Select: NM_001174147
dbSNP: rs121909487
Type: single nucleotide variant
Location: chr9:126693243 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.79
Residue 221: a DNA-binding region; the 'disordered' region

Full LMX1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nail-patella syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LMX1B p.Arg221Gln Uncertain significance ★ ⚠ same residue
LMX1B c.741+1G>A Pathogenic ★★ same condition
LMX1B c.819+1G>A Pathogenic ★★ same condition
LMX1B p.Ala236Pro Pathogenic ★★ same condition
LMX1B p.Arg223Gln Pathogenic ★★ same condition
LMX1B p.Arg231Ter Pathogenic/Likely pathogenic ★★ same condition
LMX1B p.Arg246Gln Pathogenic ★★ same condition
LMX1B p.Arg246Ter Pathogenic ★★ 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/lmx1b-p-arg221ter (accessed [today's date]).

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