Is LSS p.Arg260Pro (c.779G>C) pathogenic?

LSS p.Arg260Pro (c.779G>C) is classified Pathogenic in LSS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely pathogenic (0.9547); Absent from gnomAD v4.1; Associated with alopecia-intellectual disability syndrome 4.

What condition is associated with LSS p.Arg260Pro (c.779G>C)?

LSS p.Arg260Pro (c.779G>C) is associated with alopecia-intellectual disability syndrome 4 (ClinVar).

How common is LSS p.Arg260Pro (c.779G>C) in the general population?

LSS p.Arg260Pro (c.779G>C) is absent from gnomAD v4.1 (gnomAD).

How is Alopecia-intellectual disability syndrome inherited?

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

What do computational predictors say about LSS p.Arg260Pro (c.779G>C)?

AlphaMissense predicts likely pathogenic (score 0.9547) — an in-silico prediction, not a clinical call.

LSS p.Arg260Pro

c.779G>C · rs570157673 · VCV834066

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9547 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alopecia-intellectual disability syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9547	likely pathogenic ✓ concordant with ClinVar · top 8% in LSS
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -16.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 38 kb · p 0.045 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LSS
Protein: p.Arg260Pro
Coding: c.779G>C
MANE Select: NM_002340
dbSNP: rs570157673
Type: single nucleotide variant
Location: chr21:46216393 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 98.05 · 2 PDB
Residue 260: a UniProt-annotated variant site (in apmr4; loss of protein expression); a UniProt-annotated variant site (in apmr4; uncertain significance); 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

For Alopecia-intellectual disability syndrome (Orphanet):

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

Similar variants

LSS p.Arg260His Uncertain significance ★★ ⚠ same residue
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 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-arg260pro (accessed [today's date]).

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