Is STRADA p.Pro35Leu (c.104C>T) pathogenic?

STRADA p.Pro35Leu (c.104C>T) is classified Likely benign in STRADA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0735); Rare (popmax 0.477%, afr); Associated with polyhydramnios, megalencephaly, and symptomatic epilepsy.

What condition is associated with STRADA p.Pro35Leu (c.104C>T)?

STRADA p.Pro35Leu (c.104C>T) is associated with polyhydramnios, megalencephaly, and symptomatic epilepsy (ClinVar).

How common is STRADA p.Pro35Leu (c.104C>T) in the general population?

STRADA p.Pro35Leu (c.104C>T) is rare (popmax 0.477%, afr) (gnomAD).

What do computational predictors say about STRADA p.Pro35Leu (c.104C>T)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

STRADA p.Pro35Leu

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

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

c.104C>T · rs143559168 · VCV536764

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.477%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polyhydramnios, megalencephaly, and symptomatic epilepsy

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	donor loss · deltas
Constraint at this position
Conservation	phyloP 8.7	GERP 2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 25 kb · p 5.3e-06 · regional, not allelic
Overall
CADD	22.9	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 0.477% African / African-American · 358/75,034 alleles

Filtering AF 0.436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.42%

Overall 0.0866% 1,398/1,614,164 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.477%	210
European (non-Finnish)	0.0832%	1,202
Remaining individualsnot grpmax-eligible	0.0672%	1,488
Admixed American	0.015%	6,667
Finnishnot grpmax-eligible	0.00937%	10,670
South Asian	0.0011%	91,088

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.Pro35Leu
Coding: c.104C>T
MANE Select: NM_001003787
dbSNP: rs143559168
Type: single nucleotide variant
Location: chr17:63723317 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.46 · 4 PDB

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.Pro35= Likely benign ★ 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-pro35leu (accessed [today's date]).

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