Is LIPA p.Ser126Phe (c.377C>T) pathogenic?

LIPA p.Ser126Phe (c.377C>T) is classified Likely pathogenic in LIPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-07). AlphaMissense: likely pathogenic (0.9318); Very rare (popmax 0.000847%, nfe); Associated with cholesteryl ester storage disease.

What condition is associated with LIPA p.Ser126Phe (c.377C>T)?

LIPA p.Ser126Phe (c.377C>T) is associated with cholesteryl ester storage disease, lysosomal acid lipase deficiency (ClinVar).

How common is LIPA p.Ser126Phe (c.377C>T) in the general population?

LIPA p.Ser126Phe (c.377C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

How is Lysosomal acid lipase deficiency inherited?

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

What do computational predictors say about LIPA p.Ser126Phe (c.377C>T)?

AlphaMissense predicts likely pathogenic (score 0.9318) — an in-silico prediction, not a clinical call.

LIPA p.Ser126Phe

c.377C>T · rs1589558169 · VCV695057

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9318 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cholesteryl ester storage disease

Computational evidence

Protein change
AlphaMissense	0.9318	likely pathogenic ✓ concordant with ClinVar · top 1% in LIPA
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -13.61	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 9.6	GERP 1.9, phastCons 1
Overall
CADD	29.8	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 0.000847% European (non-Finnish) · 10/1,180,010 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,128 alleles · very rare exomes 10/1,461,864 · genomes 0/152,264 · 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: LIPA
Protein: p.Ser126Phe
Coding: c.377C>T
MANE Select: NM_000235
dbSNP: rs1589558169
Type: single nucleotide variant
Location: chr10:89228251 (GRCh38)
Structure: AlphaFold pLDDT 89.74

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

Disease context

cholesteryl ester storage disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lysosomal acid lipase deficiency

For Lysosomal acid lipase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Czech Republic)

Similar variants

LIPA c.111+1G>A Pathogenic/Likely pathogenic ★★ same condition
LIPA c.675+2T>G Likely pathogenic ★★ same condition
LIPA c.822+1G>A Likely pathogenic ★★ same condition
LIPA c.823-2A>G Likely pathogenic ★★ same condition
LIPA c.894+1G>A Pathogenic ★★ same condition
LIPA p.Ala307Asp Likely pathogenic ★★ same condition
LIPA p.Arg218Ter Pathogenic ★★ same condition
LIPA p.Arg65Ter Pathogenic ★★ 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/lipa-p-ser126phe (accessed [today's date]).

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