Is PLAA p.Leu575Pro (c.1724T>C) pathogenic?

PLAA p.Leu575Pro (c.1724T>C) is classified Uncertain significance in PLAA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.3095); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLAA p.Leu575Pro (c.1724T>C)?

PLAA p.Leu575Pro (c.1724T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PLAA p.Leu575Pro (c.1724T>C) in the general population?

PLAA p.Leu575Pro (c.1724T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PLAA p.Leu575Pro (c.1724T>C)?

AlphaMissense predicts likely benign (score 0.3095) — an in-silico prediction, not a clinical call.

PLAA p.Leu575Pro

c.1724T>C · VCV4138415

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3095 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3095	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -9.78	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 9.3	GERP 0.17, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 42 kb · p 0.094 · regional, not allelic
Overall
CADD	22.7	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 8.48e-05% European (non-Finnish) · 1/1,179,054 alleles

Overall 6.85e-05% 1/1,458,992 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: PLAA
Protein: p.Leu575Pro
Coding: c.1724T>C
MANE Select: NM_001031689
Type: single nucleotide variant
Location: chr9:26907932 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB
Residue 575: an α-helix; the pul domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLAA p.Leu575Phe Likely benign ★★ ⚠ same residue
PLAA p.Ala271Val Uncertain significance ★★ ⚠ same condition
PLAA p.Arg268Gln Uncertain significance ★★ ⚠ same condition
PLAA p.Arg373Thr Uncertain significance ★★ ⚠ same condition
PLAA p.Arg499Cys Uncertain significance ★★ ⚠ same condition
PLAA p.Arg7Ser Uncertain significance ★★ ⚠ same condition
PLAA p.Asn410Ser Uncertain significance ★★ ⚠ same condition
PLAA p.Asn520Ser 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/plaa-p-leu575pro (accessed [today's date]).

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