Is STRADA p.Arg333Trp (c.997C>T) pathogenic?

STRADA p.Arg333Trp (c.997C>T) is classified Uncertain significance in STRADA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-24). AlphaMissense: likely benign (0.1299); Ultra-rare (popmax 0.04%, amr); Associated with polyhydramnios, megalencephaly, and symptomatic epilepsy.

What condition is associated with STRADA p.Arg333Trp (c.997C>T)?

STRADA p.Arg333Trp (c.997C>T) is associated with polyhydramnios, megalencephaly, and symptomatic epilepsy (ClinVar).

How common is STRADA p.Arg333Trp (c.997C>T) in the general population?

STRADA p.Arg333Trp (c.997C>T) is ultra-rare (popmax 0.04%, amr) (gnomAD).

What do computational predictors say about STRADA p.Arg333Trp (c.997C>T)?

AlphaMissense predicts likely benign (score 0.1299) — an in-silico prediction, not a clinical call.

STRADA p.Arg333Trp

Q: How is Polyhydramnios-megalencephaly-symptomatic epilepsy syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.997C>T · rs761989598 · VCV640222

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1299 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

polyhydramnios, megalencephaly, and symptomatic epilepsy

Computational evidence

Protein change
AlphaMissense	0.1299	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.5	GERP -3.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 25 kb · p 5.3e-06 · regional, not allelic
Overall
CADD	25.0	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 0.04% Admixed American · 24/59,932 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.0023% 37/1,611,400 alleles · ultra-rare exomes 30/1,459,278 · genomes 7/152,122 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,497
African / African-American	0.004%	24,970
Remaining individualsnot grpmax-eligible	0.00321%	31,197
European (non-Finnish)	0.000678%	147,422

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: STRADA
Protein: p.Arg333Trp
Coding: c.997C>T
MANE Select: NM_001003787
dbSNP: rs761989598
Type: single nucleotide variant
Location: chr17:63704444 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.46 · 4 PDB
Residue 333: the protein kinase domain; the 'disordered' region

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

Disease context

polyhydramnios, megalencephaly, and symptomatic epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Polyhydramnios-megalencephaly-symptomatic epilepsy syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

STRADA p.Arg333Gln Uncertain significance ★ ⚠ same residue
STRADA c.36+1G>A Likely pathogenic ★★ same condition
STRADA c.37-1G>C Likely pathogenic ★★ same condition
STRADA p.Arg228Ter Pathogenic ★★ same condition
STRADA p.Ala45Val Uncertain significance ★★ ⚠ same condition
STRADA p.Arg100Gln Uncertain significance ★★ ⚠ same condition
STRADA p.Arg13Gln Uncertain significance ★★ same condition
STRADA p.Arg13Leu 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/strada-p-arg333trp (accessed [today's date]).

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