Is PLAA p.Arg499His (c.1496G>A) pathogenic?

PLAA p.Arg499His (c.1496G>A) is classified Uncertain significance in PLAA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: ambiguous (0.3893); Very rare (popmax 0.00401%, afr); Associated with neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies.

How common is PLAA p.Arg499His (c.1496G>A) in the general population?

PLAA p.Arg499His (c.1496G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PLAA p.Arg499His (c.1496G>A)?

AlphaMissense predicts ambiguous (score 0.3893) — an in-silico prediction, not a clinical call.

PLAA p.Arg499His

Q: What condition is associated with PLAA p.Arg499His (c.1496G>A)?

PLAA p.Arg499His (c.1496G>A) is associated with neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (ClinVar).

c.1496G>A · rs150012469 · VCV3065124

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies

Computational evidence

Protein change
AlphaMissense	0.3893	ambiguous
REVEL	0.202	benign-leaning
SaProt	LLR -9.83	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 42 kb · p 0.094 · regional, not allelic
Overall
CADD	32.0	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 0.00401% African / African-American · 3/74,810 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000621% 10/1,609,664 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,937
European (non-Finnish)	0.000595%	168,031

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.Arg499His
Coding: c.1496G>A
MANE Select: NM_001031689
dbSNP: rs150012469
Type: single nucleotide variant
Location: chr9:26913938 (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.Arg499Cys Uncertain significance ★★ same residue
PLAA p.Arg499Leu Uncertain significance ★ ⚠ same residue
PLAA p.Arg499Pro Uncertain significance ★ ⚠ same residue
PLAA p.Arg524Ter Likely pathogenic ★★ same condition
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

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-arg499his (accessed [today's date]).

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