Is LSS p.Pro724Arg (c.2171C>G) pathogenic?

LSS p.Pro724Arg (c.2171C>G) is classified Uncertain significance in LSS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-20). AlphaMissense: likely benign (0.1006); Very rare (popmax 0.00424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LSS p.Pro724Arg (c.2171C>G)?

LSS p.Pro724Arg (c.2171C>G) is associated with Inborn genetic diseases (ClinVar).

How common is LSS p.Pro724Arg (c.2171C>G) in the general population?

LSS p.Pro724Arg (c.2171C>G) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about LSS p.Pro724Arg (c.2171C>G)?

AlphaMissense predicts likely benign (score 0.1006) — an in-silico prediction, not a clinical call.

LSS p.Pro724Arg

c.2171C>G · rs1333454109 · VCV3121361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1006 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1006	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 38 kb · p 0.045 · regional, not allelic
Overall
CADD	25.2	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 0.00424% European (non-Finnish) · 50/1,180,046 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00316% 51/1,614,062 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00424%	23,601
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: LSS
Protein: p.Pro724Arg
Coding: c.2171C>G
MANE Select: NM_002340
dbSNP: rs1333454109
Type: single nucleotide variant
Location: chr21:46191132 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 98.05 · 2 PDB
Residue 724: a UniProt-annotated variant site (in apmr4; loss of protein expression); a UniProt-annotated variant site (in apmr4; uncertain significance)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LSS p.Ala399Val Uncertain significance ★★ ⚠ same condition
LSS p.Ala73Thr Uncertain significance ★★ ⚠ same condition
LSS p.Arg129Gln Uncertain significance ★★ same condition
LSS p.Arg260His Uncertain significance ★★ ⚠ same condition
LSS p.Arg347His Uncertain significance ★★ ⚠ same condition
LSS p.Arg547Cys Uncertain significance ★★ ⚠ same condition
LSS p.Gly383Ser Uncertain significance ★★ ⚠ same condition
LSS p.Met215Ile 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/lss-p-pro724arg (accessed [today's date]).

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