Is STRADA p.Arg346Gln (c.1037G>A) pathogenic?

STRADA p.Arg346Gln (c.1037G>A) is classified Uncertain significance in STRADA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely pathogenic (0.6932); Very rare (popmax 0.00275%, afr); Associated with polyhydramnios, megalencephaly, and symptomatic epilepsy.

What condition is associated with STRADA p.Arg346Gln (c.1037G>A)?

STRADA p.Arg346Gln (c.1037G>A) is associated with polyhydramnios, megalencephaly, and symptomatic epilepsy (ClinVar).

How common is STRADA p.Arg346Gln (c.1037G>A) in the general population?

STRADA p.Arg346Gln (c.1037G>A) is very rare (popmax 0.00275%, afr) (gnomAD).

What do computational predictors say about STRADA p.Arg346Gln (c.1037G>A)?

AlphaMissense predicts likely pathogenic (score 0.6932) — an in-silico prediction, not a clinical call.

STRADA p.Arg346Gln

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

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

c.1037G>A · rs1216340850 · VCV1488928

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00275%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polyhydramnios, megalencephaly, and symptomatic epilepsy

Computational evidence

Protein change
AlphaMissense	0.6932	likely pathogenic
REVEL	0.143	moderately benign-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Pangolin	Δ0.24	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6	GERP 0.83, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 25 kb · p 5.3e-06 · regional, not allelic
Overall
CADD	34.0	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 0.00275% African / African-American · 2/72,738 alleles

Filtering AF 0.000456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000171%

Overall 0.000692% 11/1,590,340 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00275%	36,369
Finnishnot grpmax-eligible	0.00167%	59,770
South Asian	0.00111%	90,166
European (non-Finnish)	0.000599%	166,870

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.Arg346Gln
Coding: c.1037G>A
MANE Select: NM_001003787
dbSNP: rs1216340850
Type: single nucleotide variant
Location: chr17:63704404 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.46 · 4 PDB
Residue 346: 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.Arg346Ter Pathogenic ★ 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-arg346gln (accessed [today's date]).

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