Is PLAA p.His319= (c.957C>T) pathogenic?

PLAA p.His319= (c.957C>T) is classified Benign/Likely benign in PLAA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). Low-frequency (popmax 4.33%, afr); Associated with neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies.

How common is PLAA p.His319= (c.957C>T) in the general population?

PLAA p.His319= (c.957C>T) is low-frequency (popmax 4.33%, afr) (gnomAD).

PLAA p.His319=

Q: What condition is associated with PLAA p.His319= (c.957C>T)?

PLAA p.His319= (c.957C>T) is associated with neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (ClinVar).

c.957C>T · rs112768524 · VCV780798

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.33%, afr)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.065	GERP -2.6, phastCons 0.6
Overall
CADD	6.642	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.33% African / African-American · 3,247/75,012 alleles

Filtering AF 4.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.15%

Overall 0.242% 3,900/1,613,716 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.33%	23
Remaining individualsnot grpmax-eligible	0.432%	231
Middle Eastern	0.33%	303
Admixed American	0.32%	312
South Asian	0.0307%	3,252
European (non-Finnish)	0.012%	8,308
East Asian	0.00223%	44,862

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.His319=
Coding: c.957C>T
MANE Select: NM_001031689
dbSNP: rs112768524
Type: single nucleotide variant
Location: chr9:26923260 (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.His319Asp Uncertain significance ★★ ⚠ same residue
PLAA p.His319Gln Uncertain significance ★ ⚠ same residue
PLAA p.His319Tyr 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-his319 (accessed [today's date]).

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