Is LSS p.Phe391Ser (c.1172T>C) pathogenic?

LSS p.Phe391Ser (c.1172T>C) is classified Likely pathogenic in LSS (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9627); Ultra-rare (popmax 0.0165%, mid); Associated with cataract 44.

What condition is associated with LSS p.Phe391Ser (c.1172T>C)?

LSS p.Phe391Ser (c.1172T>C) is associated with cataract 44, hypotrichosis 14 (ClinVar).

How common is LSS p.Phe391Ser (c.1172T>C) in the general population?

LSS p.Phe391Ser (c.1172T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Early onset non-syndromic cataract inherited?

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

What do computational predictors say about LSS p.Phe391Ser (c.1172T>C)?

AlphaMissense predicts likely pathogenic (score 0.9627) — an in-silico prediction, not a clinical call.

LSS p.Phe391Ser

c.1172T>C · rs1249530918 · VCV599319

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9627 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 44

Computational evidence

Protein change
AlphaMissense	0.9627	likely pathogenic ✓ concordant with ClinVar · top 7% in LSS
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -14.34	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 38 kb · p 0.045 · regional, not allelic
Overall
CADD	25.0	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

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.2e-05% 1/1,614,082 alleles · ultra-rare exomes 1/1,461,758 · genomes 0/152,324 · joint denominator

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.Phe391Ser
Coding: c.1172T>C
MANE Select: NM_002340
dbSNP: rs1249530918
Type: single nucleotide variant
Location: chr21:46210710 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 98.05 · 2 PDB
Residue 391: a UniProt-annotated variant site (in apmr4; loss of protein expression); a UniProt-annotated variant site (in hypt14; changed localization; the protein is present in the er but is also mislocalized to the cytoplasm); an α-helix

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

Disease context

cataract 44 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypotrichosis 14

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

LSS p.Arg177Gln Pathogenic/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
LSS p.Leu642Val 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-phe391ser (accessed [today's date]).

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