Is STRADA p.Ser339Leu (c.1016C>T) pathogenic?

STRADA p.Ser339Leu (c.1016C>T) is classified Uncertain significance in STRADA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: likely benign (0.0658); Ultra-rare (popmax 0.0165%, mid); Associated with polyhydramnios, megalencephaly, and symptomatic epilepsy.

What condition is associated with STRADA p.Ser339Leu (c.1016C>T)?

STRADA p.Ser339Leu (c.1016C>T) is associated with polyhydramnios, megalencephaly, and symptomatic epilepsy (ClinVar).

How common is STRADA p.Ser339Leu (c.1016C>T) in the general population?

STRADA p.Ser339Leu (c.1016C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about STRADA p.Ser339Leu (c.1016C>T)?

AlphaMissense predicts likely benign (score 0.0658) — an in-silico prediction, not a clinical call.

STRADA p.Ser339Leu

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

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

c.1016C>T · rs1214691124 · VCV1473997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0658 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polyhydramnios, megalencephaly, and symptomatic epilepsy

Computational evidence

Protein change
AlphaMissense	0.0658	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.7	GERP -1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 25 kb · p 5.3e-06 · regional, not allelic
Overall
CADD	22.4	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 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00093% 15/1,612,444 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
East Asian	0.00223%	44,840
South Asian	0.0022%	45,520
European (non-Finnish)	0.000932%	107,252

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.Ser339Leu
Coding: c.1016C>T
MANE Select: NM_001003787
dbSNP: rs1214691124
Type: single nucleotide variant
Location: chr17:63704425 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.46 · 4 PDB
Residue 339: 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 c.36+1G>A Likely pathogenic ★★ same condition
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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
STRADA p.Arg13Trp 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-ser339leu (accessed [today's date]).

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