Is LSS p.Ala121= (c.363C>T) pathogenic?

LSS p.Ala121= (c.363C>T) is classified Benign in LSS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). Common (popmax 17.6%, mid) — too common for a highly-penetrant pathogenic allele.

LSS p.Ala121=

Q: How common is LSS p.Ala121= (c.363C>T) in the general population?

LSS p.Ala121= (c.363C>T) is common (popmax 17.6%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.363C>T · rs11558754 · VCV677219

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 17.6%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -10	GERP -3.5
Overall
CADD	0.546	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 17.6% Middle Eastern · 1,064/6,062 alleles

Filtering AF 17% ClinGen BA1/BS1 input FAF95, joint · FAF99 17%

Overall 15.7% 252,558/1,613,614 alleles · common exomes 230,683/1,461,320 · genomes 21,875/152,294 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	17.6%	6
European (non-Finnish)	17.1%	6
Remaining individualsnot grpmax-eligible	15.2%	7
African / African-American	13.4%	7
Amishnot grpmax-eligible	13%	8
Admixed American	12.6%	8
Ashkenazi Jewishnot grpmax-eligible	12.4%	8
South Asian	10.2%	10
Finnishnot grpmax-eligible	9.34%	11
East Asian	9.09%	11

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.Ala121=
Coding: c.363C>T
MANE Select: NM_002340
dbSNP: rs11558754
Type: single nucleotide variant
Location: chr21:46222695 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 98.05 · 2 PDB

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

Similar variants

LSS p.Arg177Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
LSS p.Asn516Ser Likely pathogenic ★★ ⚠ same type
LSS p.Trp216Ter Pathogenic ★★ same type
LSS p.Tyr286Cys Likely pathogenic ★★ ⚠ same type
LSS p.Ala399Val Uncertain significance ★★ ⚠ same type
LSS p.Ala73Thr Uncertain significance ★★ ⚠ same type
LSS p.Arg129Gln Uncertain significance ★★ same type
LSS p.Arg260His Uncertain significance ★★ ⚠ same type

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-ala121 (accessed [today's date]).

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