Is GPAA1 p.Leu599Pro (c.1796T>C) pathogenic?

GPAA1 p.Leu599Pro (c.1796T>C) is classified Uncertain significance in GPAA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-04). AlphaMissense: likely benign (0.1521); Very rare (popmax 8.48e-05%, nfe).

How common is GPAA1 p.Leu599Pro (c.1796T>C) in the general population?

GPAA1 p.Leu599Pro (c.1796T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about GPAA1 p.Leu599Pro (c.1796T>C)?

AlphaMissense predicts likely benign (score 0.1521) — an in-silico prediction, not a clinical call.

GPAA1 p.Leu599Pro

c.1796T>C · rs1835991331 · VCV2060550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1521	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 3,391 bp · p 0.14 · regional, not allelic
Overall
CADD	26.4	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,938 alleles

Overall 6.84e-05% 1/1,461,038 alleles · very rare

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: GPAA1
Protein: p.Leu599Pro
Coding: c.1796T>C
MANE Select: NM_003801
dbSNP: rs1835991331
Type: single nucleotide variant
Location: chr8:144086055 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.48 · 4 PDB
Residue 599: an α-helix

Full GPAA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPAA1 c.1165-1C>T Likely pathogenic ★★ same type
GPAA1 c.366+1G>A Likely pathogenic ★★ same type
GPAA1 c.616+1G>T Likely pathogenic ★★ same type
GPAA1 p.Arg215Ter Pathogenic/Likely pathogenic ★★ same type
GPAA1 p.Leu291Pro Likely pathogenic ★★ same type
GPAA1 p.Ser419Ter Pathogenic/Likely pathogenic ★★ same type
GPAA1 c.1164+1A>G Uncertain significance ★★ same type
GPAA1 c.1451+5G>A Uncertain significance ★★ 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/gpaa1-p-leu599pro (accessed [today's date]).

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