Is LSS p.Pro288= (c.864G>C) pathogenic?

LSS p.Pro288= (c.864G>C) is classified Benign in LSS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 45.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with alopecia-intellectual disability syndrome 4.

What condition is associated with LSS p.Pro288= (c.864G>C)?

LSS p.Pro288= (c.864G>C) is associated with alopecia-intellectual disability syndrome 4, cataract 44 (ClinVar).

How is Alopecia-intellectual disability syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

LSS p.Pro288=

Q: How common is LSS p.Pro288= (c.864G>C) in the general population?

LSS p.Pro288= (c.864G>C) is common (popmax 45.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.864G>C · rs9980968 · VCV677174

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 45.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

alopecia-intellectual disability syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -3.3
Overall
CADD	0.078	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 45.1% African / African-American · 33,708/74,796 alleles

Filtering AF 44.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 44.5%

Overall 38.6% 621,026/1,610,250 alleles · common exomes 561,223/1,458,330 · genomes 59,803/151,920 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	53.9%	2
African / African-Americangrpmax	45.1%	2
South Asian	43.8%	2
Middle Eastern	41.6%	2
European (non-Finnish)	39.5%	3
Remaining individualsnot grpmax-eligible	38.2%	3
Finnishnot grpmax-eligible	36.7%	3
Ashkenazi Jewishnot grpmax-eligible	36.2%	3
Admixed American	27.3%	4
East Asian	12.8%	8

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro288=
Coding: c.864G>C
MANE Select: NM_002340
dbSNP: rs9980968
Type: single nucleotide variant
Location: chr21:46215713 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 98.05 · 2 PDB
Residue 288: a UniProt-annotated variant site (in apmr4; loss of protein expression); an α-helix

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

Disease context

alopecia-intellectual disability syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cataract 44

For Alopecia-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

LSS p.Arg177Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
LSS p.Asn516Ser Likely pathogenic ★★ ⚠ same condition
LSS p.Trp216Ter Pathogenic ★★ same condition
LSS p.Tyr286Cys Likely pathogenic ★★ ⚠ same condition
LSS p.Gly522Arg Uncertain significance ★★ ⚠ same condition
LSS c.551-6G>C Benign ★★ same condition
LSS c.784-6C>T Benign ★★ same condition
LSS p.Ala251Val Benign/Likely benign ★★ 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-pro288 (accessed [today's date]).

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