Is LIPA p.Ser74Phe (c.221C>T) pathogenic?

LIPA p.Ser74Phe (c.221C>T) is classified Uncertain significance in LIPA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely benign (0.1168); Ultra-rare (popmax 0.0522%, mid).

How common is LIPA p.Ser74Phe (c.221C>T) in the general population?

LIPA p.Ser74Phe (c.221C>T) is ultra-rare (popmax 0.0522%, mid) (gnomAD).

What do computational predictors say about LIPA p.Ser74Phe (c.221C>T)?

AlphaMissense predicts likely benign (score 0.1168) — an in-silico prediction, not a clinical call.

LIPA p.Ser74Phe

c.221C>T · VCV3384862

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1168 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0522%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1168	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.029	GERP -4
Overall
CADD	15.96	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0522% Middle Eastern · 3/5,752 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00756%

Overall 0.000257% 4/1,554,124 alleles · ultra-rare exomes 4/1,401,850 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0522%	1,917
European (non-Finnish)	8.88e-05%	1,125,579

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.Ser74Phe
Coding: c.221C>T
MANE Select: NM_000235
Type: single nucleotide variant
Location: chr10:89245684 (GRCh38)
Structure: AlphaFold pLDDT 89.74

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

Similar variants

LIPA p.Ser74Pro Uncertain significance ★ ⚠ same residue
LIPA c.111+1G>A Pathogenic/Likely pathogenic ★★ same type
LIPA c.539-2A>G Pathogenic ★★ same type
LIPA c.675+2T>G Likely pathogenic ★★ same type
LIPA c.676-2A>T Pathogenic ★★ same type
LIPA c.822+1G>A Likely pathogenic ★★ same type
LIPA c.823-2A>G Likely pathogenic ★★ same type
LIPA c.894+1G>A Pathogenic ★★ 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/lipa-p-ser74phe (accessed [today's date]).

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