Is PLAA p.Arg524Ter (c.1570C>T) pathogenic?

PLAA p.Arg524Ter (c.1570C>T) is classified Likely pathogenic in PLAA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-07). Very rare (popmax 0.00017%, nfe); Associated with neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies.

How common is PLAA p.Arg524Ter (c.1570C>T) in the general population?

PLAA p.Arg524Ter (c.1570C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

PLAA p.Arg524Ter

Q: What condition is associated with PLAA p.Arg524Ter (c.1570C>T)?

PLAA p.Arg524Ter (c.1570C>T) is associated with neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (ClinVar).

c.1570C>T · rs1241511703 · VCV1806265

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 14
REVEL	0.021	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.65, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,832 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,611,170 alleles · very rare exomes 3/1,459,016 · genomes 0/152,154 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,760
European (non-Finnish)grpmax	0.00017%	588,914

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg524Ter
Coding: c.1570C>T
MANE Select: NM_001031689
dbSNP: rs1241511703
Type: single nucleotide variant
Location: chr9:26910425 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB

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

Disease context

neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLAA p.Arg524= Likely benign ★ same residue
PLAA p.Ala264Thr Uncertain significance ★★ ⚠ same condition
PLAA p.Gly457Ala Uncertain significance ★★ ⚠ same condition
PLAA p.Ile356Met Uncertain significance ★★ same condition
PLAA p.Pro161Ser Uncertain significance ★★ ⚠ same condition
PLAA p.Thr114Ala Uncertain significance ★★ ⚠ same condition
PLAA p.Thr304Arg Uncertain significance ★★ ⚠ same condition
PLAA p.Tyr775His 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-arg524ter (accessed [today's date]).

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