Is LIPA p.Pro326Arg (c.977C>G) pathogenic?

LIPA p.Pro326Arg (c.977C>G) is classified Uncertain significance in LIPA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-18). AlphaMissense: ambiguous (0.3427); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with LIPA p.Pro326Arg (c.977C>G)?

LIPA p.Pro326Arg (c.977C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is LIPA p.Pro326Arg (c.977C>G) in the general population?

LIPA p.Pro326Arg (c.977C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LIPA p.Pro326Arg (c.977C>G)?

AlphaMissense predicts ambiguous (score 0.3427) — an in-silico prediction, not a clinical call.

LIPA p.Pro326Arg

c.977C>G · rs2133412088 · VCV2538482

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3427 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3427	ambiguous
REVEL	0.694	pathogenic-leaning
SaProt	LLR -10.23	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.1, phastCons 1
Overall
CADD	25.4	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: LIPA
Protein: p.Pro326Arg
Coding: c.977C>G
MANE Select: NM_000235
dbSNP: rs2133412088
Type: single nucleotide variant
Location: chr10:89215051 (GRCh38)
Structure: AlphaFold pLDDT 89.74

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LIPA p.Ala307Asp Likely pathogenic ★★ same condition
LIPA p.Leu200Pro Pathogenic ★★ same condition
LIPA p.Asp349Gly Uncertain significance ★★ same condition
LIPA p.Gln186His Uncertain significance ★★ ⚠ same condition
LIPA p.Glu269Asp Uncertain significance ★★ same condition
LIPA p.Gly45Ala Uncertain significance ★★ ⚠ same condition
LIPA p.His250Arg Uncertain significance ★★ ⚠ same condition
LIPA p.His250Pro Uncertain significance ★★ ⚠ 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-pro326arg (accessed [today's date]).

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